CN109715138A - Prostacyclin analogs preparation - Google Patents

Prostacyclin analogs preparation Download PDF

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Publication number
CN109715138A
CN109715138A CN201780056712.7A CN201780056712A CN109715138A CN 109715138 A CN109715138 A CN 109715138A CN 201780056712 A CN201780056712 A CN 201780056712A CN 109715138 A CN109715138 A CN 109715138A
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precursor formulation
component
precedent
group
precursor
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CN109715138B (en
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弗雷德里克·蒂博各
扎斯塔斯·博劳斯卡斯
卡特琳·尼斯特
马库斯·约翰森
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Camras Co
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Camras Co
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Priority claimed from GBGB1615754.7A external-priority patent/GB201615754D0/en
Priority claimed from GBGB1621277.1A external-priority patent/GB201621277D0/en
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K9/00—Medicinal preparations characterised by special physical form
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/558—Eicosanoids, e.g. leukotrienes or prostaglandins having heterocyclic rings containing oxygen as the only ring hetero atom, e.g. thromboxanes
    • A61K31/5585—Eicosanoids, e.g. leukotrienes or prostaglandins having heterocyclic rings containing oxygen as the only ring hetero atom, e.g. thromboxanes having five-membered rings containing oxygen as the only ring hetero atom, e.g. prostacyclin
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    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
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    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/5578—Eicosanoids, e.g. leukotrienes or prostaglandins having a pentalene ring system, e.g. carbacyclin, iloprost
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
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    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
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    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
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    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
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    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract

The present invention relates to a kind of injectable precursor formulation, it includes: a) monoacyl lipid, diacyl lipid or at least one of three acyl group lipids and/or tocopherol；B) optionally at least one phosphatide；C) at least one bio-compatible organic solvent；And d) at least one prostacyclin analogs or its salt；Wherein the precursor formulation forms or is capable of forming at least one liquid crystalline phase structure after contacting with excessive aqueous fluids.The composition can additionally comprise polar co-solvent.It provides especially for managing the treatment method of pulmonary hypertension (PAH), severe PAH, Raynaud's disease, ischemic and related disorders and the corresponding uses of composition.Also provide includes the application device of preparation and the medicine box including described device.

Description

Prostacyclin analogs preparation
Technical field
The present invention relates to preparation precursor (the preceding systems to the composition in situ for generating the control release for activating agent Agent) and the method treated with the preparation.In particular, the present invention relates to amphipathic components and at least one prostacyclin (prostacyclin) precursor formulation of analog is gone through phase transformation after being exposed to aqueous fluids such as body fluid, is consequently formed Control release composition.
Background technique
Many bioactivators including drug, nutrients, vitamin etc. have " functional window ".That is, depositing Can be observed these reagents can provide a certain biological effect after a certain concentration range.When in the appropriate part in body Concentration (such as in part or as by illustrated by serum-concentration) when dropping to certain level or less, no beneficial effect can return Because in reagent.Similarly, usually exist when being higher than its by making concentration increase not obtain the top concentration of further benefit It is horizontal.In some cases, undesirable or even dangerous effect can be generated by so that concentration is increased above specified level.
Some bioactivators have permanent biological half-life and/or broad functional window, therefore can aperiodically apply With to maintain functional living being concentration after substantive period (such as 6 hours to a couple of days).In other cases, clearance rate Be higher and/or functional window be it is narrow, be to maintain biological concentration in this window therefore, need with a small amount of side Formula carries out periodically (or even continuous) administration.This is desirable in non-oral application (such as parenteral administration) approach or must Want when can be especially difficult because self application can be it is difficult, lead to inconvenient and/or bad compliance.Institute It, will be for advantageously after needing entire period locating for activity all to mention under treatment level for single administration in the case of stating For activating agent.
The activating agent with high clearance rate and short-half-life of one particular category is the analog of prostacyclin and it.Before Column ring element is an endogenous member of eicosanoid (eicosanoid) family, and is related in including platelet activation, blood Pipe diastole and regulating blood pressure it is several during.When referring to synthetic source substance, prostacyclin is also referred to as Epoprostenol (epoprostenol), and the term is used interchangeably herein.
Epoprostenol is checked and approved by FDA for treating pulmonary hypertension (PAH) in nineteen ninety-five.PAH is to be characterized in that average Pulmonary arterial pressure (mPAP) is >=25mmHg, with the potential mortality illness of normal pulmonary arterial wedge pressure (PAWP) (≤15mmHg). However, it needs usually to pass through central venous catheter because Epoprostenol itself has the Half-life in vivo less than 1 minute Carry out continuous administration.For intravenous therapy Cycloprostin with(GlaxoSmithKline) it is sold.From Since 2008, the epoprostenol formulation of ambient-temp-stable (Actelion Pharmaceuticals) also it can be used. It is believed that be worldwide estimated to be 100,000 to 200,000 individuals is influenced by PAH.
Known several prostacyclin analogs with longer half-life, including iloprost (iloprost) (Bayer) and treprostinil (treprostinil).Treprostinil was checked and approved in 2002 by FDA, and have 2.9 to 4.6 hours plasma half-lives.Although there is longer half-life, continuous intravenous infusion or regular skin compared to Epoprostenol Lower application treprostinil is usually still necessary.Intravenous therapy needs to be surgically inserted into central venous catheter, carries infection It is and certainly uncomfortable for the patient with thrombosis risk.Epoprostenol can also pass through sucking or oral route To apply.However, these approach provide the lower intergal dose of Epoprostenol compared to intravenous route.Therefore, they can not Suitable for all patients.
(United Therapeutics Corporation) is that one kind is designed to intravenously Or the treprostinil preparation of continuous subcutaneous injection.Continuous subcutaneous injection is realized by means of micro infusion pump.Although this is solved To the huge relevant some problems of pumping unit, but it is still undesirable, and also, it is recommended to be patient can quick obtaining it is spare Infusion pump.
Although regular subcutaneous administration solves intravenous or continuous subcutaneous administration, oral or inhalation route to a certain extent Disadvantage, but site of administration pain is the major obstacles (being subjected to by 85% patient) in the case where Most patients, and The almost all of treprostinil to treat for being attributed to adverse events is caused to exit (total 23% in the group that studies for a long period of time).It arrives So far, this is handled by suitable position selection in possible degree.Position pain is former after position changes Reach peak value in it, and in some cases, it is for 4 weeks or more long using single position can be helpful and safe.
In the presence of the obvious needs of the following preparation to prostacyclin analogs, the preparation storage when be it is stable, can Do not need by central venous catheter or by continuous subcutaneous administration come continuous administration under applied, be not susceptible to it is mechanical therefore The risk of barrier and/or can be compared with being applied under small frequency, while leading to smaller part position pain compared to existing subcutaneous preparations.The present invention Solve some or all of these deficiencies.
The patient for being subjected to PAH treatment usually requires therapeutic dose and maintains one considerable period, and usually requires to continue to be permitted Multiple moons are perhaps treated for many years.Therefore, allow to load and control after the longer term reservoir system of release larger dose Significant advantage more than conventional delivery system will be provided.
In this regard, the polymeric delivery systems containing treprostinil have been developed, 1 clinical trial phase has such as been subjected to TransCon treprostinil (Ascendis Pharma).TransCon treprostinil is designed to the every of treprostinil Day self primary application subcutaneous injection liquid, and be based on polymeric delivery systems is based especially on the poly- of poly- (oxazoline) or PEG Close object.TransCon treprostinil is intended to effect identical as the prostacyclin analogs offer of continuous infusion, but uses and more pacify Complete and preferably administration method is dropped with position relevant to current parenteral administration approach reaction and bloodstream infection risk It is low.
Commonly used in degrade slow release preparation polylactic acid, polyglycolic acid and polylactic acid be total to glycolic acid polymer be also to The reason of a certain stimulation of few some patients.In particular, these polymer usually contain the acid impurities of a certain ratio such as Lactic acid and glycolic will stimulate injection site in application.When polymer then decomposes, lactic acid and glycolic are that degradation produces Object, so that causing further to stimulate.
Although by TransCon treprostinil in patient comfort and frequency of administration (daily one to a certain extent It is secondary) smaller aspect provides potential advantages, even with the polymer such as PEG for not resolving into acid impurities, polymer system It also tends to high viscosity, it is therefore desirable to the product of relatively brief duration is injected and/or only provided by wide needle. PEG, which grafts on activating agent such as treprostinil, usually increases bio-longevity, but may interfere with combination, and cannot currently provide Active product will be kept by last from days between injection.Due to the application of wide needle and/or the combined effect of irritation content, institute Usually it is greater than desirable degree in degree with the formation for not accommodating connective scar tissue at site of administration.This is being mentioned Be increased in the case where treprostinil preparation out because injection be it is at least daily rather than weekly or more long period carries out 's.Therefore, after permanent duration for the treatment of, it is necessary to carry out multiple irritation application at a small number of positions, or utilize many It is uncomfortable with caused widely distributed subject in the case where position.
Obviously, it will can be easy to apply by narrow needle for being to provide for advantage, thus make the patient during program uncomfortable Reduce and cause the system with low viscosity of smaller part position pain, such as homogeneous solution, fine particle dispersion liquid or L2Phase. This be easy to be applied in patient will using self application program and can daily self administered several times (as using several The case where existing treprostinil to treat agent) when be especially important.The duration for having a couple of days is provided, but is applied multiple enough It is miscellaneous thus it need the lasting preparation that is handled by health care professional all will not be for all patients be more than daily The advantage of self application is carried out twice or daily, and may be costly.Offer give the long enough long duration so that It will be great excellent for having reason to go to a doctor at healthy professional to reach the preparation of application and/or can be easy to the preparation of self application Gesture.Reducing the time of health care professional or patient before actually application is also major issue.
From the point of view of drug delivery viewpoint, polymer storage tank composition, which generally also has, only receives relatively low drug loading Amount, and have the shortcomings that " outburst/sluggishness " discharges overview.Especially when in the form of solution or prepolymer in application, polymerization The property of matrix leads to the release outburst of the initial drug in initial application composition.This is followed by one low release period, when When the degradation of matrix starts, finally it is followed by rate of release and increases to obtain required lasting overview.This outburst/sluggishness release is general The bulk concentration outburst that condition can lead to immediately activating agent after administration is more than functional window, is then returned during sluggish period It is down to the bottom of functional window, lasting functional concentration is consequently reached and continues one period.Obviously, from functional and toxicology From the point of view of viewpoint, this outburst/sluggishness release overview is undesirable, and can be dangerous.Due to " peak value " point when not Benefit effect has risk, so this can also limit available equilibrium concentration.In addition, the presence in lag phase can be needed in storage tank Supplement administration is carried out to be in sub- function in the concentration of the activating agent provided from storage tank with duplicate injection during the starting period for the treatment of Maintenance therapy dosage when energy property.
Delivery formulations are controlled usually to be generated by bio-compatible polymer with such as implantation material or injectable bead form.It is poly- Object microspheres preparation is closed to generally have to apply by means of usually having 20 specifications or broader large needle.Due to being usually polymer The property of the polymerization drug delivery system used of suspension, so this is necessary.It will can be easy to for being to provide for advantage through narrow needle It applies, the system with low viscosity that thus reduces patient's discomfort during program, such as homogeneous solution, fine particle Dispersion liquid or L2Phase.Being easy to be applied in patient will carry out when self is applied being especially important, and work as health care professional people Member also reduces their burden when being administered.
In the case where certain existing reservoir systems, in addition the manufacture of PLGA microballon grain and suspension is significant difficulties.It is special For fixed, because bead is particle, they generally can not be sterile filtered, and in addition, because PLGA copolymer exists It is melted under high temperature, so they cannot be heat-treated to reach aseptic.Therefore, it is necessary to sterilely carry out complicated manufacture work Skill.
Other problems in the case where biodegradable polymer microsphere include recovery complexity before injection with And storage stability is limited, both due to the aggregation and degradation of delivery system and/or activating agent.
The slow release composition based on lipid of certain peptides has been described.For example, WO2006/131730 discloses GLP- A kind of 1 and the like lipid reservoir system.This is a kind of highly effective preparation, but the activating agent that can be included in preparation Concentration be limited to its dissolubility.Obviously, greater activity agent concentration allow there is a possibility that the storage tank product duration it is longer, produce Product maintain higher systemic concentration and product has smaller volume injected, and the factor all has weight in the appropriate case Big advantage.It therefore, with substantial worth will be to establish the activating agent of higher concentration to be included in the storage tank system based on lipid What the slave loading of mode employed in agent and identified activity agent and delivery system, stability, manufacture and/or control discharged It is particularly effective combination from the point of view of viewpoint.
Present inventor is it has been determined that by providing in low viscosity phase such as molecular solution or L2(reverse micelle) phase includes At least one neutrality monoacyl lipid, diacyl lipid or three acyl group lipids and/or tocopherol, optionally at least one phosphatide, extremely The precursor formulation of few a kind of bio-compatible organic single methanol solvent and at least one prostacyclin analogs or its salt, can produce solution Many insufficient precursor formulations of certainly known treprostinil preparation, and it can be applied to provide prostacyclin analogs Control release.Surmount existing prostacyclin analogs system by using specific components, can produce to have with the ratio that carefully selects The combination of the property of the performance of agent, and provide more than known treprostinil composition such asOr The depot preparation of the advantage of TransCon treprostinil.
In particular, precursor formulation shows highly advantageous release overview, easily fabricated, can be sterile filtered, be had Low viscosity (allows usually to reach the application being easy with lesser degree pain by narrow needle), and it is living to allow to be incorporated to high-caliber biology Property agent (therefore potential allow using small amount of composition and/or activating agent), need shallow injection and/or form tool in vivo There is the required non-laminar storage tank composition of " low outburst " release overview.Composition can also be dropped by nontoxic, biological tolerable and biology Solution substance formed, the composition can by single intramuscular or subcutaneous injection rather than central venous catheter or continuous subcutaneous injection To apply, and applied suitable for self.In addition precursor formulation can have extremely low irritation level in injection, and in preferable case Under, do not have stimulation (including of short duration stimulation) at injection site.Compared to " slow release " preparation equally proposed, preceding system Agent can be applied compared with small frequency, so as to cause better patient's compliance and/or the lesser thorn for being attributed to repetition and frequently applying Swash.
Invention formulation generates non-laminar liquid crystalline phase after administration.Non-laminar phase is used in the delivering of bioactivator Structure (such as non-laminar liquid crystalline phase) is relatively well accepted now.A kind of most effective lipid reservoir system is described in In WO2005/117830, and a kind of highly preferred lipid storage tank is described in that file.If however, for realizing Dry aspect has the depot preparation for improving performance, still allows some leeway, and in particular, surprising improvement can be by carefully selecting It is realized with the range of component disclosed in optimization previous research and ratio.
The present composition be more than the advantage of polymer formulations such as PLGA microsphere include easily fabricated (including sterilizing), Processing and character of use initial release low with activating agent (" low outburst overview ") combine.This can be defined as in administration in one week Plasma concentration is the area under the curve of entire curve (from time zero relative to area under time graph during first 24 hours of phase To it is infinite or from time zero to last sampling time point measurement or extrapolation) less than 50%, more preferably less than 40%, and most Preferably smaller than 30%.In addition, it can be defined as the internal maximal plasma concentration of activating agent after body preparation before the injection It (Cmax) is at most 10 times of mean plasma concentration (Cave) during treatment period, preferably up to 8 times, and most preferably It is at most 5 times (i.e. Cmax/Cave≤10, preferably≤8, more preferably≤5).
Summary of the invention
The present invention provides a kind of comprising lipid excipients, organic alcohol solvent and prostacyclin analogs and optional group certain The appropriately combined pharmaceutical preparation divided can be used as storage tank precursor formulation (being referred to herein as precursor formulation for brevity) and use In the one or more the demand of solution.Present inventor has determined that by optimizing these components, can produce with highly advantageous The storage tank composition of the prostacyclin analogs of the especially treprostinil of combination of properties and corresponding precursor formulation.
In the first embodiment, the present invention provides a kind of precursor formulation, it includes:
A) monoacyl lipid, diacyl lipid or at least one of three acyl group lipids and/or tocopherol；
B) optionally at least one phosphatide；
C) at least one bio-compatible organic solvent；With
D) at least one prostacyclin analogs or its salt；
Wherein the precursor formulation optionally but is preferably formed as or is capable of forming at least one after contacting with excessive aqueous fluids Kind liquid crystalline phase structure.
In the preferred embodiment for being applicable to all aspects of the invention, it is suitable that prostacyclin analogs contain 3,4- Formula condenses pentamethylene ring, the OH group at 1 of the pentamethylene ring and the C1-10 base at 2 of the pentamethylene ring Group, these structures are defined in more detail herein.Prostacyclin analogs can for example with such as indicate herein Formulas I, Ia, Ib or Ic.
Prostacyclin analogs of the invention will include in the molecule usually carboxylic moiety, or can be its salt.However, current Column ring element analog do not contain acid unit, and can not forming salt when, term " free acid " as used herein " should be interpreted that Neutral molecule (such as neutral esters).
In another preferred embodiment of the present, prostacyclin analogs (free acid) have the molecular weight less than 500g/mol, And not polypeptide.
In another preferred embodiment of the present, prostacyclin analogs (free acid) are the 0.1 to 10% of precursor formulation, preferably Exist under 0.2 to 6% level.In one embodiment, prostacyclin analogs (free acid) such as 0.2 to 5%, Exist under the level of 0.5 to 5%, especially 0.2 to 4% or 0.75 to 4%.
In another preferred embodiment of the present, prostacyclin analogs include following or are made up of: treprostinil (TPN) or its salt, preferably treprostinil sodium salt.
In a preferred embodiment, component c) is comprising at least one solvent selected from the group being made up of or by least A kind of solvent composition selected from the group being made up of: alcohol, amine, amide, sulfoxide and/or ester.
In a preferred embodiment, c) comprising following or be made up of: the mixture of ethyl alcohol or ethyl alcohol and propylene glycol, Preferably, wherein the ratio of ethyl alcohol and PG are 1:1 to 10:1, more preferably 1.5:1 to 8:1, most preferably 2:1 to 5:1 (such as About 3:1).
In another preferred embodiment of the present, as defined herein, under 25 DEG C and 60%RH, after 3 months, preferably exist After 6 months, especially after 12 months, for measuring as the activating agent measured by HPLC, precursor formulation has at least 96%, preferably at least 97%, especially at least 98% stability.
In another preferred embodiment of the present, under 40 DEG C and 75%RH, after 1 month, preferably after 3 months, especially It is after 6 months, and for being measured after storage by the activating agent of HPLC measurement, precursor formulation has at least 96%, preferably at least 97%, especially at least 98% stability.
In a particularly preferred embodiment,
Component a) includes GDO or is made of GDO,
Component b) includes Soybean PC or is made of Soybean PC；
Component c) includes ethyl alcohol, and optionally includes propylene glycol；And
Component d) includes following or is made up of: treprostinil or its salt (such as sodium salt).
In second aspect, the present invention relates to precursor formulations as defined herein to lasting application prostacyclin analogs Purposes.
On the other hand, the present invention, which provides, is used as the real according to first of medicament (such as treating illness as described herein) The composition applying the precursor formulation of scheme or being obtained by making the precursor formulation be exposed to excessive aqueous fluids.
On the other hand, the present invention provides a kind of method for treating people or non-human mammalian subject comprising Precursor formulation as defined herein is applied to the subject.
In one embodiment, treatment method (and corresponding uses and other aspects) is a kind of for treating people or non- The method of people's mammalian subject (person especially in need).In another embodiment, treatment method (and corresponding uses With other aspects) it is a kind of method for treating at least one illness selected from the following: pulmonary hypertension (PAH), PAH phase Close chronic obstructive pulmonary disease (COPD), severe Raynaud's disease (Raynaud ' s disease), ischemic and related disorders.
In one embodiment, treatment method is related to every 1 to 60 day, and preferably every 1,2,3,7,14,21,28,30 or 60 day (such as ± 3 days or under any circumstance ± 20%), most preferably every 7 (± 1) day or every 14 (± 2) day or every 30 (± 3) day are applied With precursor formulation as defined herein.
In one embodiment, treatment method is related under 0.005 to 2.5mg/kg/ weeks level, preferably 0.01 to 1mg/kg/ weeks, the prostacyclin analogs or its salt are especially applied under 0.015 to 0.7mg/kg/ weeks level.
On the other hand, it the present invention relates to a kind of precursor formulation as described herein, is used to treat as described herein It (is used in the case where being included in all diseases, illness, dosage, method or application as described herein and application program) in method.
On the other hand, the present invention relates to precursor formulations as defined herein to manufacture for forming storage tank in vivo The purposes of medicament, the storage tank is for treating at least one illness selected from the following: pulmonary hypertension (PAH), PAH are related COPD, Raynaud's disease, ischemic and related disorders.
On the other hand, the present invention provides a kind of pre-filled application device containing precursor formulation as defined herein.
On the other hand, the present invention relates to a kind of medicine boxs comprising application device as defined herein preferably includes automatic Syringe, cylindrantherae and/or pen.
Detailed description of the invention
The release in vitro overview that (a) at any time of the preparation that Fig. 1 is selected from table 1 and the square root (b) of time change.
The result of Fig. 2 changes of weight of rat during carrying out investigative research administration using preparation B1 and B2 is (referring to reality Apply example 2 and table 2).
The viscosity of preparation L-AA selected by Fig. 3 (referring to embodiment 3 and table 6)
The release in vitro overview (cumulative release percentage) (a) of Fig. 4 preparation N, P, Q, R and S, wherein 0-20% discharges area Domain is in extended view (b).
After Fig. 5 is balanced in an aqueous medium, X-ray diffractogram of the preparation L-S at 25 DEG C, 37 DEG C and 42 DEG C.
After Fig. 6 is balanced in an aqueous medium, X-ray diffractogram of the preparation T-AA at 25 DEG C, 37 DEG C and 42 DEG C.
The mean plasma concentration of Fig. 7 TPN in rat after applying preparation EE, FF, GG or HH.
The release in vitro overview (cumulative release percentage) of Fig. 8 preparation FF, EE, X and HH.
Fig. 9 is in the precursor formulation single subcutaneous injection that will contain 3,15,22.5 and 30mg TPN to male and female beagle dogs In after average treprostinil plasma concentration v. time overview.
Precursor formulation single subcutaneous injection to the male and female for containing 3,15,22.5 and 30mg TPN is being compared lattice by Figure 10 Average treprostinil AUC after in dog0-168hValue.
Specific embodiment
Invention formulation generates non-laminar liquid crystalline phase after administration.Non-laminar phase is used in the delivering of bioactivator Structure (such as liquid crystalline phase) is relatively well accepted now.The most effective general lipid reservoir system of one kind is described in In WO2005/117830, and a kind of lipidic matrix suitable for being used in the present invention, institute are briefly described in that file The complete disclosure for stating patent is hereby incorporated herein by accordingly.About retouching for the most advantageous phase structure to the preparation It states, it should be noted that the discussion in WO2005/117830, and especially it should be noted that its page 29.
Unless otherwise instructed, otherwise all specified with weight throughout all % herein.In addition, when context allows, instruction Weight % be include all components indicated herein total precursor formulation %.Regardless of using acid or its salt, prostacyclin The weight percent of analog is all calculated the weight based on free acid.Precursor formulation can be optionally substantially only by herein referring to Component (when in place including the additional optional component indicated in the following and appended claims herein) composition shown, and In one aspect, it is grouped as completely by described group.When preparation is indicated as " being substantially grouped as by certain groups herein ", at this time Specified ingredients provide the required property of that preparation, and such as specified ingredients account at least the 95% of preparation at this time, preferably at least 98%.
Preferably, precursor formulation of the invention be molecular solution or have L2Phase structure (before administration).In application Afterwards, precursor formulation forms non-laminar (such as liquid crystal) phase.This phase transformation usually by from physiological environment absorb aqueous fluids caused by, Show as mentioned in this article.If although previously having been determined in WO2012/160213 there are single methanol solvent, then careful control amount Water can be tolerated, it will be appreciated that after application, precursor formulation is exposed to a large amount of aqueous fluids.In general, at least equal volume amounts Aqueous fluids contact after, precursor formulation will form non-laminar phase.
Present inventor is it has now surprisingly been that determination can by proper choice of lipid composition and prostacyclin analogs and biology Type, absolute magnitude and the ratio of compatible organic solvents can cause releasing for the storage tank composition formed by precursor formulation of the invention It is highly advantageous to put property, and is better than existing treprostinil depot preparation.In particular, single administration prostacyclin analogs If the remote super existing treprostinil storage tank of release duration release duration, internal maximal plasma concentration is only It is the smaller multiple of the mean concentration or even Cmin during medicine-feeding period.
Component a)-acyl group lipid/tocopherol
The preferred scope of component a) is 15-85wt%, preferably 20-80%, preferably 30-60wt%, preferably 35- 55%, all 38-52% in this way, especially 38 to 52%.In some embodiments, about 43% (such as 41 to 45%) level It is particularly preferred.
The preferred scope of component b) is 15-85wt%, preferably 20-80%, preferably 30-60wt%, preferably 35- 55%, all 38-52% in this way, especially 38 to 52%.In some embodiments, about 43% (such as 41 to 45%) level It is particularly preferred.
The ratio of a:b is usually 40:60 to 60:40, preferably 45:55 to 55:45, and more preferably 47:53 to 53: 47.The ratio of about 50:50 (such as ± 2) is highly effective.
If the component " a " indicated herein includes monoacyl lipid or one of diacyl lipid and/or tocopherol or more Person.Most preferably, component a) includes monoacyl lipid or diacyl lipid or is made of monoacyl lipid or diacyl lipid, because This has one or two nonpolar " tail portion " group.For acylglycerol (such as monoacylglycerol or two acyls in the present invention Base glycerol) it is used as pure compound that will be not generally formed non-laminar liquid crystalline phase structure in water at 25 DEG C.
In one embodiment, component a) can be monoacyl lipid.Monoacyl lipid containing polarized " head " group and One nonpolarity " tail groups "." head " group can be glycerol, two glycerol, saccharide part (such as based on inositol and glucosyl group Part)；And the ester of polyalcohol, such as acetic acid esters or succinate.The monoacyl lipid of one preferred classes is such as de- The ester of the hexitan of water D-sorbite.In this term, " hexitan " expression HOCH2(CHOH)4CH2OH hexitol, It is cyclized due to the water of loss monovalent to form five-membered ring or hexatomic ring, preferably five yuan of furanose rings.Anhydrosorbitol Sugar alcohol is a particularly preferred head group.Head group is preferably connected to tail groups by ester bond.It is suitable in following discussion Close tail groups.
In a particularly preferred embodiment, component a) includes following or is made up of: at least one diacyl lipid, Preferably diacylglycerol (DAG).Diacyl lipid includes polar head group as described above and is preferably connected by ester bond It is connected to two nonpolarity tail groups of the polar head group.The most preferably polar head group of diacyl lipid is sweet Oil.
Non-polar group can have the carbon atom of identical or different number, and can be saturation or insatiable hunger each independently Sum.The example of non-polar group includes C6-C32Alkyl and alkenyl usually exist with the ester-formin of long-chain carboxylic acid.These are often Often described by referring to carbon atom number in carbochain and degree of unsaturation number.Therefore, CX:Z instruction have X carbon atom with The hydrocarbon chain of Z degree of unsaturation.Example particularly including lauroyl (C12:0), myristoyl (C14:0), palmityl (C16: 0), phytane acyl group (C16:0), palmitoleoyl (C16:1), stearyl (C18:0), isostearoyl base (C18:0), oleoyl (C18:1), anti-oleoyl (C18:1), sub-oleoyl (C18:2), linolenyl (C18:3), arachidonic acyl group (C20:4), Behenyl acyl group (C22:0) and two myristoyl bases (C24:9).Therefore, fatty acid of the typical apolar chain based on natural esters lipid, packet Include caproic acid, octanoic acid, capric acid, lauric acid, myristic acid, palmitinic acid, phytanic acid, palmitolic acid, stearic acid, oleic acid, elaidic acid, Asia Oleic acid, linolenic acid, arachidonic acid, behenic acid or tetracosanoic acid or correspondent alcohol.It is preferred that apolar chain be palmitinic acid, stearic acid, Oleic acid and linoleic acid, especially oleic acid.
The mixture of any number of monoacyl lipid or diacyl lipid is used as component a).Preferably, this group It point will include at least part of C18 lipid (such as with one or more (i.e. one or two) C18:0, C18:1, C18:2 Or the DAG of C18:3 non-polar group), such as dehydrated sorbitol mono-fatty acid ester (SMO), diolein (GDO) and/or Dilinolein (GDL).One highly preferred example is comprising at least 50% preferably at least 80%, and even comprising big The DAG of 100%GDO in cause.
Because GDO and other monoacylglycerols and diacylglycerol are derived from natural product, usually deposit In " pollution " lipid etc. with other chain lengths of a certain ratio.In one aspect, GDO as used herein is accordingly used in indicating Any class of trade GDO (i.e. business purity GDO) with associated impurity.These impurity can be separated and be removed by purifying, But if grade is consistent, then this is seldom necessary.However, if necessary, then " GDO " can be substantially chemical pure Net GDO, all in this way at least 80% is pure, and preferably at least 85% is pure, and more preferably at least 90% pure GDO.
The compound of all or part of one alternative or additional preferred classes as component a) is tocopherol.Such as Used herein, term " tocopherol " is used to indicate nonionic lipid tocopherol, usually referred to as vitamin E and/or its any be suitble to Salt and/or analog.Suitable analog will be that those of phase behaviour, nontoxicity and phase transformation are provided after being exposed to aqueous fluids, The feature for being characterized in the present composition.The analog will be not generally formed at 25 DEG C in water as pure compound Non-laminar liquid crystalline phase structure.Most preferred tocopherol is the tocopherol itself having following structure.Obviously, especially when this is from day When right source purifying, the non-tocopherol " pollutant " of small scale may be present, but this will be not enough to change advantageous phase behaviour or nontoxic Property.In general, by weight, tocopherol preferably comprises at most 5% for containing at most 10% non-tocopherol anologs compound, And most preferably at most 2%.
Tocopherol
In one embodiment of the invention, component a) is substantially by tocopherol, tocopherol especially as shown above Composition.
The preferred component combination of component a) is that (for example, at least a kind of C16 of DAG- is extremely at least one diacylglycerol C18DAG, such as GDO) with the mixture of at least one tocopherol.By weight, the mixture includes 2:98 to 98:2 fertility Phenol: DAG, such as 10:90 is to 90:10 tocopherol: DAG, and especially includes these compounds of 20:80 to 80:20.Tocopherol With other acylglycerols it is all as discussed herein in those of the similar mixtures of any one be also suitable.
Component b)-phosphatide
Optional components " b " in preferred lipidic matrix of the invention are at least one phosphatide.As component a), this Component includes polar head group and at least one non-polar tail group.Component a) and b) between difference essentially consist in polarity Group.Therefore, nonpolar moiety can be compatibly derived from above for the component a) fatty acid considered or correspondent alcohol.Phosphatide (example Such as PC) it will contain there are two non-polar group.Again, C18 group is preferred, and can be suitble to non-polar group with any other Especially C16 moiety combinations.It can be not form non-layer in water at 25 DEG C as pure compound for the phosphatide in the present invention Those of shape liquid crystalline phase structure.Alternatively, can be to form non-laminar liquid crystalline phase in water at 25 DEG C for the phosphatide in the present invention Those of structure such as hexagonal liquid crystal phase.
Phospholipid moiety, or even be more suitable for than any diacylglycerol part, it may originate from natural origin.It is suitble to phospholipid sources packet Include ovum, heart (such as cor bovinum), brain, liver (such as beef liver) and the plant origin including soybean.The source can provide can One or more ingredients of component b comprising any mixture of phospholipids.
Polar head group suitable for component b) includes phosphatidyl choline, phosphatidyl-ethanolamine, phosphatidylserine and phosphorus Acyl inositol.Most preferably phosphatidyl choline (PC) and/or phosphatidyl-ethanolamine (PE).In WO2013/038460 and Display can lead to storage tank robustness using the PE of at least 50 weight % of phosphatide total amount and improve in WO2013/083459.
Learn the lipid slow release matrix based on three acyl group lipids when being exposed to aqueous fluids from WO2016/066655 Storage tank composition can be formed in the presence of not needing phospholipid fraction, but phosphatide also may be present.Therefore, in one embodiment, Component a) includes three acyl group lipids, is made of three acyl group lipids or is substantially made of three acyl group lipids, and component b) is to appoint Choosing.However, in another embodiment, if fruit component a) is including greater than 50% monoacyl lipid or diacyl lipid or extremely The mixture of a kind of few tocopherol or any of these components, then phospholipid fraction b) will preferably exist.In an embodiment In, component a) include less than 50% (such as 0 to 49% or 0.1 to 45%) three acyl group lipid the total amount of component a) (be based on), and And component b) exists (such as under the 20 to 80wt% of precursor formulation or in the other amounts such as indicated in various embodiments herein Under).
In the present invention, particularly preferably component b) includes one or more PC or is made of one or more PC.It lifts For example, at least 50% head group of component b) should be PC, preferably be more than 65% head group, especially more than 85% or more than 90%.Any single PC or PC mixture from these or other source can be used, but include Soybean PC or The mixture of ovum PC is that height is suitble to.PC component preferably comprises at least 50% Soybean PC or ovum PC, further preferably at least 75% Soybean PC or ovum PC, and most preferably essentially pure Soybean PC or ovum PC.
In an embodiment for being applicable to all aspects of the invention, component b) includes PC or is made of PC.It is excellent Selection of land, PC are derived from soybean.Preferably, PC includes 18:2 fatty acid as main fatty acid component, with 16:0 and/or 18:1 rouge Fat acid is as secondary fatty acid component.These are present in PC under ratio preferably between 1.5:1 and 6:1.With about 60- 65%18:2,10 to 20%16:0,5-15%18:1, rest part are mainly that the PC of other 16 carbon and 18 carbon fatty acids is preferred , and represent Soybean PC.
In the alternative but same preferred embodiment for being equally applicable to all aspects of the invention, PC component can be wrapped Dioleoyl PC (DOPC) containing synthesis.It is believed that this provides increased stability, thus for need to stablize long term storage and/or The composition in vivo with permanent release period will be particularly preferred.In this embodiment, PC component preferably comprise to Few 50% synthesis dioleoyl PC, further preferably at least 75% synthesis dioleoyl PC, and it is most preferably substantially pure Net synthesis dioleoyl PC.Remaining any PC is preferably highly Soybean PC as above or ovum PC.
In one embodiment, precursor formulation of the invention at least partly includes that synthesis DOPC (has at least The PC of 95%PC head group and at least 90% oleoyl (C18:1) acyl group), and at least six moon, more preferably at least 12 Month, and after most preferably at least 24 months, there is the storage stability at 15-25 DEG C, be defined as less than 5% activity Agent degradation, as measured by HPLC.
Because precursor formulation of the invention will be applied to subject to reach control delivery of prostacyclin analogs, weight What is wanted be each component is bio-compatible.It in this regard, is high for the preferred lipidic matrix in precursor formulation of the invention It spends advantageous, because PC and DAG are both well tolerable, and resolve into be naturally present in body of mammals in vivo In component.
Synthesis or highly purified PC such as dioleyl phosphatidyl choline (DOPC) and palmitoyloleoyl phosphatidyl gallbladder Alkali (POPC) and other various high-purity PC as described herein are that height is appropriate as all or part of of component b).
In a highly preferred embodiment, component b) is by having the polar head comprising at least 95% phosphatidyl choline " high-purity " PC of the phosphatide composition of group and each independently two acyl chains with 16 to 20 carbon, wherein at least one Acyl chain has at least one degree of unsaturation in carbochain, and there are at most four degrees of unsaturation in two carbochains.
In general, this can be to have the C16 of 0 to 3 degree of unsaturation extremely at least 95%PC head group and at least 95% The PC of C20 acyl chain.
Synthesizing dioleoyl PC is most preferably 1,2-dioleoyl-sn-glycero-3-phosphocholine, and other are synthesized PC component includes DDPC (1,2- didecyl docosahexaenoyl-sn-glycero -3- phosphocholine)；DEPC (bis- mustard acyl group-sn- glycerol of 1,2- Base -3- phosphocholine)；DLOPC (bis- sub-oleoyl-sn- glyceryl -3- phosphocholine of 1,2-)；DLPC (bis- lauroyl of 1,2- Base-sn- glyceryl -3- phosphocholine)；DMPC (bis- myristoyl-sn- glyceryl -3- phosphocholine of 1,2-)；DOPC(1, 2- dioleoyl-sn- glyceryl -3- phosphocholine)；DPPC (bis- palmityl-sn- glyceryl -3- phosphocholine of 1,2-)； DSPC (1,2- distearyl acyl group-sn- glyceryl -3- phosphocholine)；(1- myristoyl -2- palmityl-sn- is sweet by MPPC Oil base 3- phosphocholine)；MSPC (- 3-phosphocholine of 1- myristoyl-2- stearyl-sn- glyceryl)；PMPC (1- palm fibre - 3-phosphocholine of palmitic acid acyl group-2- myristoyl-sn- glyceryl)；POPC (1- palmityl -2- oleoyl-sn- glyceryl - 3- phosphocholine)；PSPC (- 3-phosphocholine of 1- palmityl-2- stearyl-sn- glyceryl)；SMPC (1- stearyl- - 3-phosphocholine of 2- myristoyl-sn- glyceryl)；SOPC (1- stearyl -2- oleoyl-sn- glyceryl -3- phosphoric acid Choline)；With SPPC (1- stearyl -2- palmityl-sn- glyceryl -3- phosphocholine) or any combination thereof.
Component a) and particularly advantageous combination b) are SMO and PC, GDO and PC, especially GDO and Soybean PC and/or " high Purity " PC.Each component is that those of the individual components instruction any combination is measured herein suitable for combined appropriate amount. When context allows, this is also applied for any group of subassembly indicated herein.
The ratio of component a:b is in the range of 40:60 to 60:40.Preferably, a:b ratio is more excellent in 45:55 to 55:45 It is selected in the range of 47:53 to 53:47.Most preferably, a:b ratio is about 50:50, such as 48:52 to 52:48.
In one embodiment, the absolute magnitude of component a) will be 40 to 47%, the absolute magnitude of component b) will be 40 to The ratio of 47%, a:b will be 48:52 to 52:48, and the amount of component c) will be 5 to 20%, preferably 8 to 12%, wherein component c) By under the ratio of 2.5:1 to 3.5:1 ethyl alcohol and propylene glycol form, and component d) will (be based on 2.5 to 50mg/ml Free acid), such as Treprostinil sodium under 5 to 50mg/mL (being based on free acid).
Component c)-bio-compatible organic solvent
The component c) of precursor formulation of the invention is bio-compatible organic solvent.Because precursor formulation will be in application (example As in vivo) storage tank composition is generated usually after contacting with aqueous fluids later, so it is desirable that this solvent can It is resistant to, and can be mixed with aqueous fluids by subject, and/or spread or dissolve precursor formulation out and enter aqueous fluids In.Therefore, it is preferred for having at least water-soluble solvent of moderate.
Component c) includes to be selected from the bio-compatible organic solvent for the group being made up of or be made up of by being selected from The bio-compatible organic solvent composition of group: alcohol, amine, amide including single methanol solvent and diol solvent and polyol solvent, Sulfoxide or ester.Particularly preferably component c) includes single methanol solvent or is made of single methanol solvent.
Component c) may include the component of two or more inventories from the above solvent, especially single methanol solvent and be selected from The solvent of amide, sulfoxide or diol solvent.It is not that any solvent of single methanol solvent can all be referred to herein as cosolvent.Work as presence When two or more solvents, it is especially preferred combination be ethyl alcohol and amide (such as ethyl alcohol and NMP), ethyl alcohol and sulfoxide (such as Ethyl alcohol and DMSO) or ethyl alcohol and diol solvent or polyol solvent (such as ethyl alcohol and PG).One highly preferred solvent combination is Ethyl alcohol and PG, especially when the ratio of ethyl alcohol and PG is 1:5 to 20:1, preferably 1:1 to 10:1, more preferably 1.5:1 to 8: 1, most preferably 2:1 to 5:1 are (when for example, about 3:1, such as 2.8:1 are to 3.2:1).Component c) may include following or by with the following group At: or mixtures thereof ethyl alcohol, propyl alcohol, isopropanol, benzyl alcohol.Most preferably, component c) includes ethyl alcohol or is made of ethyl alcohol.
The amount of component c) will have considerable impact to several features in precursor formulation.In particular, viscosity and rate of release (and duration) will significantly change with solvent levels.Therefore, the amount of solvent will at least be enough to provide low viscosity mixtures, but It will in addition be determined in order to provide required rate of release.This can be determined by conventional method in view of following embodiment.In general, The solvent levels of 1 to 30%, especially 2 to 25%, which will provide, is suitble to release and viscometric properties.This will preferably 2 to 20%, it is excellent Choosing is 5 to 15%, and the amount of about 10% (such as 10 ± 3%) is highly effective.These levels include as component c) Any cosolvent as mentioned above existing for a part.
As indicated above, the amount of component c) will at least be enough to provide component a), b), c) and d) in precursor formulation of the invention Low viscosity mixtures (such as molecular solution), and be readily able to determine by standard method and be combined for any specific components Component c) amount.
Phase behaviour can by such as visually observation with polarization microscopy, X-ray scattering and diffractive technology, nuclear magnetic resonance, with And the technology of low-temperature transmission electron microscopy (low temperature TEM) combination is analyzed to look for solution, L2Or L3Phase or liquid crystalline phase, or such as The dispersion segment of the phase is looked in the case where low temperature TEM.Viscosity can directly be measured by standard approach.As described above, suitable When functional viscosity is to may achieve effective injection, and especially may achieve the viscosity of aseptic filtration.This is readily able to as mentioned in this article Show and is assessed.
Component a), b) and c) one highly preferred combination are GDO, Soybean PC and/or " high-purity PC " and ethyl alcohol, or SMO, Soybean PC and ethyl alcohol.Other preferred combinations include GDO/SPC/ ethyl alcohol/DMSO, GDO/SPC/ ethyl alcohol/NMP and GDO/SPC/ Ethyl alcohol/PG.As indicated above, each component is that the individual components any combination are referred to herein suitable for combined appropriate amount Those of show amount.
Component c) as used herein can be single solvent or the mixture of suitable solvent, but will usually have low viscosity. This is important, because a critical aspects of the invention are that it provides the precursor formulation with low viscosity, and is suitble to solvent Main function be to make the reduction of this viscosity.This reduce by be solvent relatively low viscosity influence and solvent combine with lipid The combination of the influence of interaction of molecules between object.One of present inventor is observation is that low viscosity as described herein is oxygen-containing The lipid part of solvent and composition has highly advantageous and unexpected interaction of molecules, thus in addition small size Non-linear viscosity is provided in the case where solvent to be reduced.
The viscosity of " low viscosity " solvent composition c) (single solvent or mixture) should be usually the at most 18mPas at 20 DEG C. This is preferably at most 15mPas, the at most 10mPas more preferably at 20 DEG C at 20 DEG C, and is most preferably at 20 DEG C At most 7mPas.
Determine that with " polar solvent " or " cosolvent " such as glycol or water alcohol to be applied in combination molten in WO2012/160213 Agent allows the performance of certain control release compositions based on lipid to significantly improve.In particular, it has been observed that addition glycol is (all Such as propylene glycol) or water allow alcohol ratio increase without negatively affecting release overview, and/or allow discharge overview improve and/ Or allow the useful load of activating agent higher.
Exemplary co-solvents will have corresponding to they highly polar compare for high dielectric constant.Therefore, it is suitble to Cosolvent will usually have at least 30 dielectric constant more preferably at 25 DEG C at least 28 at 25 DEG C.The suitable reality of height Example include water (about 80), propylene glycol (about 32), dimethyl sulfoxide (about 47) and n-methyl-2-pyrrolidone (NMP, about 32).
In some embodiments, the one of component c) especially appropriate solvent combination includes single methanol solvent and is selected from by following The cosolvent of the group of composition: amide, sulfoxide or glycol.One particularly preferably combination is ethyl alcohol and amide, ethyl alcohol and sulfoxide or ethyl alcohol And glycol.Particularly preferably combination is ethyl alcohol and propylene glycol (PG)；Ethyl alcohol and dimethyl sulfoxide (DMSO)；And ethyl alcohol and N- methyl- Pyrrolidones (NMP).
When it is present, usually precursor formulation is greater than 1 weight %, such as 2-15% by the suitable amount of cosolvent, especially It is 4-12.%, especially 4-10wt%.The combination of single methanol solvent and cosolvent as component c) has in the compositions of the present invention There are potential advantages.In particular, by include can be with a certain cosolvent of single methanol component miscibility, can be at injection site by alcohol Slightly feel generally to be eliminated caused by inclusion.Therefore, in one embodiment, single methanol component: the ratio of cosolvent Rate can be in 30:70 to 90:10, more preferably in 50:50 to 80:20, especially in the range of 60:40 to 80:20.The amount of component (w/w) approximately equal is that height is appropriate.
Component d)-prostacyclin analogs
Precursor formulation of the invention contains at least one prostacyclin analogs or its salt.Prostacyclin and conjunction are shown below At analog beraprost (beraprost), Epoprostenol, iloprost and treprostinil.
Selection to prostacyclin analogs is not particularly critical for the present invention, as long as it is treated needed for realizing Effect, and the phase behaviour of precursor formulation is not negatively affected.
However, in general, prostacyclin analogs component d) will have one or more following characteristics.Firstly, it is preferably It synthesizes non-peptide.Secondly, it preferably has less than 500amu, the preferably shorter than molecular weight of 400amu (free acid).Third, it is preferably Include C3-12 alkyl, alkenyl or alkynyl and the cis- condensed 5- or 6-membered ring of 3,4- with 1- hydroxyl substituent, at 2 Pentamethylene unit.Referring to structure is given above, number used will readily appreciate that.4th, prostacyclin analogs preferably wrap Containing carboxylic acid and/or ester units.Such as can by beraprost, Epoprostenol, iloprost and treprostinil structure seen in, These structure features are shared between prostacyclin and known synthetic analogues beraprost, iloprost and treprostinil.
For all aspects of the invention prostacyclin analogs can particularly including formula (I) prostacyclin analogs:
Wherein:
N is 1 or 2；
X is O, CH2, CHF or CF2；
R is H, R10, or polyethylene glycol (PEG) is connected to by connection unit；
R1 is the substituted or unsubstituted alkyl of H, F or C1-C10, alkenyl or alkynyl；
R2 ' is the substituted or unsubstituted alkyl of H, F or C1-C6, alkenyl or alkynyl；
R2 is saturation or the substituted or unsubstituted alkyl of unsaturation C1-12, alkenyl or alkynyl, preferably saturation or unsaturated C1-10 group；
R5 is X (CH2)aCO2R9, wherein X is O or CH2, a is 0 to 4, preferably 1 or 2, and
Wherein R9 is the substituted or unsubstituted alkyl of H, C1-C6, alkenyl or alkynyl or biologically acceptable cation；
R8 and R8 ' is H, F or C1-C6 alkyl, alkenyl or alkynyl, preferably H each independently；
N is 1 or 2；
And:
All R4 and R4 ' group are all the substituted or unsubstituted alkyl of H, F or C1-C6, alkenyl or alkynyl each independently； And
R5 ' is the substituted or unsubstituted alkyl of H, F or C1-C6, alkenyl or alkynyl, preferably H；
Or:
R5 ' and adjacent R 4 and/or R4 ' group 5 yuan, 6 yuan or 7 yuan substituted or unsubstituted rings of formation, preferably 6 member rings, And most preferably substituted or unsubstituted 6 yuan of aromatic rings；And
Any additional R4 and/or R4 ' group are all the substituted or unsubstituted alkyl of H, F or C1-C6, alkenyl each independently Or alkynyl.
R10 is such as group of protectiveness part or prodrug moiety.It is suitble to protectiveness part and/or prodrug moiety includes Ester is included in those defined in following sections.
In a preferred embodiment, if n is 1, structure has formula (I-a)
Wherein R4 and R4 ' is H, F or C1-C6 alkyl, preferably H each independently；And
R5 ' is H, F or C1-C6 alkyl, preferably H；
Wherein remaining substituent group as above defines formula (I)；
Or there is structural formula (I-b)
Wherein substituent group as above defines formula (I)；
In another preferred embodiment of the present, if n is 2, structure has formula (I-c)
Wherein R4 and R4 ' is H, F or C1-C6 alkyl, preferably H each independently；
Wherein remaining substituent group as above defines formula (I).
It is particularly preferred embodiment below.
For each in formula (I), (Ia), (Ib) and (Ic):
X is preferably O or CH2；
R1 is preferably H；
R2 preferably includes the OH group for the third carbon atom for being connected to the R2 from pentamethylene unit；
R2 ' is preferably H；
R4 and R4 ' is all preferably H or and R5 ' formation phenol ring；
R8 and R8 ' is preferably H；
In addition to the above preferred embodiment, for formula (Ia):
R2 is preferably unsaturation C6-C12 group, preferably unsaturation C8-C10 group, especially includes being connected to from ring The OH group of the third carbon atom of the R2 of pentane unit.It is more preferred still that R2 is
Even further preferably, R2 is:
Or R2 is:
Or R2 is:
Even further preferably, R2 is:
Or R2 is:
R5 ' is preferably H；
X is O or CH2；
R5 is preferably CH2CH2CH2CO2R9, wherein R9As defined above, R5 especially CH2CH2CH2CO2H；
R is preferably H.
In one embodiment, prostacyclin analogs can be iloprost.
For formula (Ib):
R2 is preferably unsaturation C6-C12 group, preferably unsaturation C8-C10 group, especially includes being connected to from ring The OH group of the third carbon atom of the R2 of pentane unit.It is more preferred still that R2 is
Even further preferably, R2 is:
X is preferably O；
R5 is preferably CH2CH2CH2CO2R9, wherein R9As defined above, R5 especially CH2CH2CH2CO2H；
R is preferably H.
In one embodiment, prostacyclin analogs can be beraprost.
For formula (Ic):
X is preferably CH2；
R is preferably H, or is connected to PEG by linking group；
R2 is preferably saturated C6-C10 group, preferably saturation C8 group, especially includes being connected to from pentamethylene unit R2 third carbon atom OH group.It is more preferred still that R2 is:
Or R2 is:
Even further preferably, R2 is:
Or R2 is:
R5 is preferably OCH2CO2R9, wherein R9As defined above, R5 is most preferably OCH2CO2H。
In one embodiment, prostacyclin analogs can be treprostinil.
In any structural formula for herein referring to show, when there are OH groups (especially as group OR or as group R2's Element) when, this group can be protected with prodrug forms.The prodrug is usually hydrolyzed in vivo so as to dissociate the part-OH again It is raw, and may include ester and/or acetal groups.Particularly suitable prodrug is such as integrally incorporated in the US9394227 of this paper for R1 With described in the position R2.
In said case, when the part OH is protected with prodrug forms, any-OH group all can be independently with-O- R10 group form is protected, and wherein R10 is independently one of following when occurring for each time:
R11It is all independently alkyl, alkylaryl, naphthenic base, heterocycle, aryl or heteroaryl when occurring for each time, it is each From can optionally be substituted；
R12And R13It is all independently hydrogen, C1-C6 alkyl or C3-C6 naphthenic base or R when occurring for each time12And R13And it The carbon atom that is connected form C3-C6 cycloalkyl ring；
R14It is all independently hydrogen, R when occurring for each time11、-C(═O)R11、-C(═O)OR11Or-C (═ O) NR15R16；Or
R14And R12Or R13The atom connected together with them is formed together heterocycle；
R15And R16It is all independently hydrogen, alkyl ,-alkylaryl, naphthenic base, heterocycle, aryl or miscellaneous when occurring for each time Aryl；Or
R15And R16And the nitrogen-atoms that they are connected forms heterocycle or heteroaryl ring；
J is independently 0 to 4 integer when occurring for each time；And
M is independently integer of 1 to 10 when occurring for each time.
In certain embodiments, R11 be all independently when occurring for each time methyl, ethyl, propyl, isopropyl, butyl, Isobutyl group, sec-butyl or tert-butyl；R12 and R13 is independently hydrogen, methyl, ethyl, propyl or isopropyl when occurring for each time Base；R14 is independently hydrogen or R11 when occurring for each time；J is 0；And m is 1.
When p- OH group is replaced, this can be independently at any-OH group, or preferably will be in all free-OH At group.In a preferred embodiment, owning-OH groups existing for a part as OR or as group R2 all will be with Identical prodrug-O-R10 group is protected.In some embodiments, existing any or each-OH group is all substituted into Ester.
Can be used for replacing "-OH " group with provide some particular instance esters of prodrug include ethyl ester, isopropyl ester or Succinate.
Prostacyclin analogs d) is in all embodiments of prodrug wherein, and the preferably described prodrug is formulated in Comprising in precursor formulation below:
A) monoacyl lipid, diacyl lipid or at least one of three acyl group lipids and/or tocopherol；
B) optionally at least one phosphatide；With
C) at least one bio-compatible organic solvent；And
And wherein the precursor formulation forms or is capable of forming at least one liquid crystal after contacting with excessive aqueous fluids Phase structure.
In particular, prostacyclin analogs d) is in all embodiments of prodrug wherein, before preferably described Medicine is formulated in comprising in precursor formulation below:
A) diacyl lipid, most preferably diolein (GDO)；
B) at least one phosphatide, preferably phosphatidyl choline (PC)；With
C) at least one bio-compatible organic solvent；And
And wherein the precursor formulation forms or is capable of forming at least one liquid crystal after contacting with excessive aqueous fluids Phase structure.
In all embodiments, it is preferably according to the geometry of the loop system of formula (I):
In a preferred embodiment, prostacyclin analogs have the molecular weight less than 500g/mol.
Most preferably, component d) includes following or is made up of: beraprost, Epoprostenol, iloprost or song Prostacyclin (such as Epoprostenol, iloprost or treprostinil), most preferably treprostinil.Forefront can also be used Any biologically acceptable salt of ring element analog.When the amount of component d) is provided with weight percent, unless context It additionally allows for, otherwise it is intended that the weight based on free acid.In a particularly preferred embodiment, component d) include it is following or It is made up of: treprostinil free acid (TPN) or its salt, most preferably treprostinil sodium salt (TPN (Na)).It is also contemplated within Use the upper permissible alcohol of ester derivant such as ethyl ester or other biological (including glycol or polyhydroxy-alcohol such as propylene glycol or sweet Oil) ester, and this can provide be applicable to control prostacyclin analogs release and/or its biological half-life it is " preceding Medicine " effect.
Instruction optionally employs " connection unit " or " connector " herein, especially on the position " R " of formula (i) or other structures Corresponding site at.This connector can for example form ester bond at the R of position, and can all can be according to need by means of any one of them It is subject to substituted or unsubstituted straight chain, branch and/or cyclic alkyl and/or alkenyl part, ester group, amide group, amido Group, ether group, mercaptan, thioesters and annulus such as pyrrolidines and pyrrolidine-diones (such as 3- sulfanyl -2,5- pyrrolidines two Ketone) group engages major part such as peptide, protein, PEG group.
Other prostacyclin analogs suitable for the present invention include all prostacyclin receptor agonists such as color benefit Western pa (Selexipag).
Based on prostacyclin analogs free acid, component d) is with 0.1 to 15%, preferably with 0.1 to 10%, such as with 1 to 12%, especially exist with 2 to 8% amount.In some embodiments, the level of prostacyclin analogs can be 4 to 8%.This A little levels are particularly suitable for treprostinil.
The surprising discovery of present inventor is that the release duration of prostacyclin analogs such as treprostinil is strong Depending on the amount of activating agent and both the property of solvent composition c).Therefore, the releasing properties of storage tank can be by changing these parameters One or more of tune.
In addition, the release that the surprising discovery of present inventor is prostacyclin analogs such as treprostinil can be by suitable When selection preparation solvent and solvent ratio effectively control.
In general, in monoacyl lipid and/or diacyl lipid (such as GDO) together with phosphatide such as phosphatidyl choline one Rise depot preparation in the case where, activating agent release mainly by preparation phase behaviour control, the phase behaviour transfer mainly by The property and ratio of lipid composition control.However, in the context of the present invention, present inventor has determined that releasing properties, and especially It is the maximum bulk concentration (Cmax) reached after administration, can be subject to by selection solvent and solvent ratio beneficial to optimization. In one embodiment, for example, the present invention provides precursor formulation of the invention, and wherein component c) includes ethyl alcohol and the third two Alcohol basically comprises ethyl alcohol and propylene glycol or is made of ethyl alcohol and propylene glycol, and wherein the ratio of ethyl alcohol and PG is in 1:1 and 10:1, More preferably in 1.5:1 to 8:1, most preferably in 2:1 to (for example, about 3:1) between 5:1.In particular, compared to wherein compared to PG, there are equal quantities or the preparations of less amount of ethyl alcohol, have both ethyl alcohol and PG (such as respectively at least 0.5%), wherein second The preparation of amount of the amount of alcohol greater than PG can provide lower Cmax (i.e. lower " peak value " bulk concentration).The control to releasing properties System has tremendous importance in the case where slow release preparation, and will not be expected and can be mentioned by selection solvent ratio For.
About the level of component d), Fig. 4 a illustrates that TPN contains 1.53 from the matrix in GDO/PC/EtOH (45:45:10) The release in vitro that the preparation of TPN (Na) between to 7.76% carries out.Under the useful load of 7.76%TPN (Na), preparation shows " outburst " feature, i.e., about 50% TPN (Na) in the period of about 24 hours after discharge, and 6.17% and be lower than 6.17% Level under, the release of TPN (Na) is gently much.It is the present invention that outburst overview can be changed only by appropriate selection component Precursor formulation potential extremely applicable characteristic.In one embodiment, these can by selection solvent and solvent ratio come It influences.
It in one embodiment, can be in accordance with especially when it is desirable that preparation provided short-term release after 1 to 3 day It is desirable that with 6.5% or bigger, especially with 6.7% or bigger or 7% or bigger especially TPN or TPN (Na) forefront The level of ring element analog is operated.However, in general, the horizontal of prostacyclin analogs will be usually at most 5 weights Measure %, preferably up to 4 weight % (such as 0.5 to 4 weight %, such as about 1 weight %, about 2 weight % or about 3 weight %).
After 1 to 3 day period provide the short-term release storage tank that is released effectively can use ethyl alcohol as sole component c) down to Few 11%, preferably at least 12%, especially prepared at least 13% level.Alternatively, ethyl alcohol and sulfoxide especially ethyl alcohol and The mixture of DMSO especially can be used as component c) with 20% or smaller, such as with 10 to 20% with 12 to 18% amount.At this In embodiment, ethyl alcohol: the ratio of sulfoxide is in the range of 20:80 to 60:40 (w:w), the especially model in 30:70 to 50:50 In enclosing.
When it is desirable that providing the gentler release of prostacyclin analogs, for example, for a Zhou Shichang or every two weeks or Monthly duration storage tank, can be it is desirable that be such as grasped with less than 6.5% with 6.2% or smaller level d) Make, especially 5.5% or smaller or 5% or smaller is desirable.As indicated above, the horizontal of prostacyclin analogs will Usually at most 5 weight %, preferably up to 4 weight % (such as 0.5 to 4 weight %, such as about 1 weight %, about 2 weight % Or about 3 weight %).Therefore, the precursor formulation for applying once a week or once every two weeks preferably includes before 1 to 7% Column ring element analog, such as 1 to 3%, especially TPN or TPN (Na).
Such as it the long-term release storage tank being released effectively is provided weekly or every two weeks can be made with ethyl alcohol after the period greater than 5 days It is prepared under less than 11% such as 10% or smaller level for sole component c).Alternatively, ethyl alcohol and diol solvent or polyalcohol The solvent especially mixture of ethyl alcohol and PG or second alcohol and water can especially be used with 5 to 20% with 5 to 15% amount, wherein second Alcohol: PG or ethyl alcohol: for the ratio of water in the range of 40:60 to 60:40 (w:w), the level of about 50:50 is particularly preferred.About The ethyl alcohol of the amount of the PG of 2.5% amount and about 7.5% is highly effective.
In one aspect, each embodiment can be optionally containing antimicrobial or suppression microorganism agent herein comprising antibacterial Agent and preservative.The reagent includes benzalkonium chloride, metacresol, benzyl alcohol or other phenol preservatives.Such as this field can be used In known typical concentration.
Beyond referring to that the additional component for component a) to those of d) component will be preferably with 0 to 5 weight when being implicitly present in It measures % (such as 0.01% to 5%), preferably at most 2 weight %, and more preferably exists with the amount of at most 1 weight %.
In one embodiment, component a) and b) (take into account these components is intrinsic any impurity in properties) Constitute at least the 95% of the lipid composition of composition.Preferably, at least the 99% of the total lipid content of precursor formulation is by component a) And it b) forms.Preferably, the lipid composition of precursor formulation is substantially formed by component a) and b).
Application
Precursor formulation of the invention is usually formulated to be subject to parenteral administration.This application will be not usually intravascular side Method, but will preferably subcutaneous (s.c.), intracavitary or intramuscular (i.m.) method.Importantly, precursor formulation of the invention has They are not needed in advantage that is intravenous or being applied by continuous subcutaneous injection.Preferably, application is not intravenous or continuous Subcutaneous administration.
In general, application will by injection carry out, the term be used to indicate herein wherein such as by needle, conduit or Needleless (needle-less/needle-free) syringe come make preparation pass through skin any method.It is preferred that parenteral administration By intramuscular or subcutaneous injection, most preferably carried out by being subcutaneously injected.One important feature of the present composition is that it can It is applied by both intramuscular route and subcutaneous route and other approach, without toxicity or significant local effect, especially It is not lead to significant position pain.It is also suitable for intracavitary application.It is injected compared to (depth) intramuscular, subcutaneous injection has deep Degree is smaller, and to the lesser advantage of the pain of subject, and is technically most suitable for situation of the present invention, because it makes to be easy to Injection is combined with low local side effects risk.The one of present inventor is surprising observation is that by subcutaneous injection, preparation is after can Prediction period provides the sustained release of activating agent, and in general, compared to existing prostacyclin analogs preparation, invention formulation So that can get long too much release duration.
Preferred lipid precursor preparation of the invention provides non-laminar liquid crystal after being especially exposed to aqueous fluids in vivo Storage tank composition.As used herein, term " non-laminar " is used to indicate positive liquid crystalline phase or more preferably anti-liquid crystalline phase is (such as anti-vertical Side's phase or hexagonal phase) or L3 phase or any combination thereof.Term liquid crystal indicate all hexagonal liquid crystal phases, all cubic liquid crystal phases and/ Or its all mixture.Otherwise six side as used herein indicates " just " six side or six side of negation (preferably unless otherwise specified, Anti- six side), and any cubic liquid crystal phase of " cube " instruction.By referring to description provided herein and embodiment and reference WO2005/117830, skilled reader in identification there are those of appropriate phase behaviour Composition Aspects will not have a difficulty, but for Best compositing range is the ratio of wherein component a:b as described in previous section for phase behaviour.About 50:50 (such as ± 2) ratio is highly preferred, most preferably about 50:50 for most of preparations.
It is important to understand that precursor formulation of the invention has low viscosity.Therefore, these precursor formulations must not be in Any bulk liquid crystal phase, because all liquid crystalline phases are all compared to the viscosity that can pass through syringe or similar injection dispenser therefor With significant higher viscosity.Therefore, precursor formulation of the invention will be in non-liquid crystal state, such as solution, L2Or L3Phase, it is special It is not solution or L2.The L as used in this paper entire chapter2Mutually preferably " it is swollen " L2Phase contains greater than 5wt%, preferably greater than 7%, And most preferably greater than 9% organic solvent (the component c) with reduction viscosity effect.In L2The preceding system of the invention of phase Dosage form is at one group of preferred precursor preparation.
As used herein, term " low viscosity mixtures " or " low viscosity precursor formulation " are used to indicate and can be easy to subject Application, and the mixture for being easy to be applied by means of standard syringe and needle device in particular.This can be for example by can It is distributed by small gauge needle from 1ml disposable injection syringe to indicate.Preferably, low viscosity mixtures can be passed through by manual pressure The needle of 19 specifications, preferably by more preferably being distributed by 23 specifications (or being most preferably even 27 specifications) needle less than 19 specifications. In a particularly preferred embodiment, low viscosity mixtures should can pass through standard sterile filter membrane such as 0.22 μm of syringe mistake The mixture of filter.Be suitble to viscosity typical range will be for example at 20 DEG C 10 to 1000mPas, more preferably 10 to 800mPas, and most preferably 200 to 700mPas.
After application, the precursor formulation for being preferably based on lipid of the invention is subjected to from low viscosity mixtures to high viscosity The phase structure transformation of (usually with tissue adherence) storage tank composition.In general, this will be swollen L from molecule mixture2And/or L3The transformation of or mixtures thereof such as anti-six side of opposite one or more (high viscosity) liquid crystalline phases or cubic liquid crystal phase.Other phase transformations It can also occur after administration.Obviously, complete phase transformation is not required by operation of the invention, but the table of at least applied mixture Surface layer will form liquid crystal structure.In general, this changes the surface region at least applied preparation (with air, body surface And/or that part for directly contacting of body fluid) for will be quick.This will be most preferably after several seconds or several minutes (such as 1 Second until 30 minutes, preferably of up to 10 minutes, more preferably 5 minutes or shorter time).The rest part of composition can pass through expansion It dissipates and/or more slowly makes mutually to become liquid crystalline phase with surface region dispersion.
Under without being bound by theory, it is believed that after being exposed to excessive aqueous fluids, precursor formulation of the invention is lost Or all including organic solvent (such as passing through diffusion), and from physical environment (such as vivo environment) absorb aqueous flow Body.For lipid precursor preparation, at least part preparation preferably generates non-laminar phase structure, especially liquid crystalline phase structure.Big In most cases, these non-laminar structures are high viscosities, and are not easy to dissolve or be dispersed in vivo environment.The result is that Entirety " storage tank " only with limited body fluid exposure area is generated in vivo.In addition, because non-laminar structure has large-scale polarity Region, nonpolar regions and borderline region make activating agent dissolve and stablize, and protect these so lipid storage tank is highly effective Activating agent is from mechanism of degradation.With the storage tank composition formed by precursor formulation after a couple of days, several weeks or several months period by It gradually degrades, activating agent is gradually discharged and/or diffused out from composition.Because the environment in storage tank composition is protected relatively Shield, so precursor formulation of the invention is highly suitable for the activating agent with relative brevity biological half-life.
Compared to generally there is no under water containing organic solvent composition, by will at least 2% (for example, at least 5%) polar co-solvent (especially at least 5%PG, water, NMP or DMSO) is incorporated in precursor formulation, it is believed that through injecting precursor It can be enhanced at the surface of preparation to the rate of the phase transformation of non-laminar (such as liquid crystal) phase.Therefore, the performance of gained storage tank obtains To improve, and realize the further control of the release to activating agent.
The highly effective protection activity agent of reservoir system formed by invention formulation allows release period from degradation Extend.Therefore, invention formulation can provide the internal storage tank of prostacyclin analogs, need only application in every 1 to 60 day primary. Typical administration interval will be for example every 1,2,3,7,14,21,28,30 or 60 day, and can be systematically or occasionally with a small amount of (examples Such as with ± 3 days, or with ± 20% in any appropriate situation) changed.Highly preferred frequency of administration includes every 7 (± 1) It or every 14 (± 2) day or every 30 (± 3) day.In one embodiment, the forefront ring containing reduced levels for comparing The preparation of plain analog (such as 0.5 to 2.0%) once a week, once every two weeks or can be applied monthly, and have There is the preparation of the prostacyclin analogs (such as by weight, 2.5% to 4% or bigger) of higher level can once a week or more Continually primary, every 2 days such as every 3 days it is primary or applied daily.
Obviously, and if composition will not in accordance with the needs of patient comfort and compliance in longer stable release period It is self application type, then needing to spend healthy professional's less time.When composition will be self application type, suffer from Person's compliance can be added by (such as every 7 days, optionally ± 1 day) weekly or monthly (such as 28 or 30 days every (optionally ± 7 days)) application To assist so that will not forget to need to apply.Continuous administration is not needed or daily more than the system once applied even if being to provide It is healthy and free from worry that agent also will greatly improve in this area patient in many cases.
It is applicable to all aspects at of the invention one, but especially can be applied to the reality for the treatment of method and corresponding uses Apply in scheme, administration dosage and frequency can gradually rise with latent disease (such as any in those of instruction disease herein Person) progress it is corresponding.Therefore, the prostacyclin analogs of 1mg/ weeks or 5mg/ weeks dosage are for the subject in early stage It can be enough, and the form that these dosage weekly, every two weeks or can be applied monthly as needed provides, such as every 4 weeks 1.5ml is injected at 10mg/ml will give 3.75mg/ week mean dose, and can be in early days enough for disease.Work as disease When disease progression, dosage can increase to every two weeks 1ml (at 10mg/ml) (5mg/ weeks), weekly 0.75ml (7.5mg/ weeks) and 1.0ml/ weeks (10mg/ weeks).Subsequent increase can be realized then by the preparation of higher concentration, such as every two weeks 1.0ml 30mg/ml preparation (15mg/ weeks), by making frequency and volume increase to such as weekly 1.0ml (30mg/ weeks) Lai Shenggao, then If necessary, then increasing to multiple applications weekly.
Under using continuous infusion, it is known that about 1 to 4ng/kg/ minute predose of prostacyclin analogs is used as Beginning infusion dosage be it is typical, correspond to about 10 to 40 μ g/kg weekly, especially for Epoprostenol and its salt (such as sodium Salt) for.The dosage forms the initial dose for being suitable for invention formulation, can then be titrated until realizing and be suitble to function Effect/tolerability balance.For treprostinil (and salt such as sodium salt), suitable initial dose is usually the starting of Epoprostenol About half of dosage corresponds to 0.5 to 2ng/kg/ minute (about 5 to 20 μ g/kg weekly).Again, can using upwards titration until Determine suitable dosage.
One importance of method of administration of the invention is that while that precursor formulation as described herein will preferably last at least 7 days The control release of prostacyclin analogs is provided, but frequency of administration is more rapidly than this.So that it takes up a position, for example, being infused in single Penetrate after precursor formulation of the invention the plasma concentration of prostacyclin analogs at 7 days can drop to after that application Plasma concentration is not less than 10 at the end of 1st day-3, preferably not less than 10-2, and most preferably not less than 10-1.Disease early stage, This control release performance of 7 day duration product can be enough, and significant advantage is provided in terms of that.However, Compared to every 7 days, the application of this product with releasing properties as described can be repeated more frequently (such as one Week twice, it is 3 days every, every 2 days or daily).This application will meaningfully occur before the effect failure of the first application.So And multiple injection (such as at multiple positions) long duration time product as described herein is provided to prostacyclin analogs blood Starch concentration will also bigger leveling, and allow in the case where not needing big volume injected use high dosage.
So that it takes up a position, for example, twice a week injection 1.0ml 30mg/ml preparation will under without any large-scale injection with And provided 60mg/ weeks under extremely stable release overview, it is put down because " peak value " of a release corresponds to the stabilization previously applied It is steady horizontal.In this way, there is name 7 days or the more long duration (such as above-mentioned 7 days release overview) it is of the invention before Body preparation can biweekly, it is 3 days every, every 2 days or provide when being subject to using to be done as progression of disease requirement daily it is higher and The prostacyclin analogs of steady concentration.
Another significant advantage of storage tank precursor of the invention is that they are stable homogeneous phases.That is, they can be in room Considerable period (preferably at least six moon, especially at least 12 months) is stored under interior or refrigerator temperature, and without mutually separating. It also is provided with benefit storage and applies easily, this allows by referring to the species of individual subject, age, gender, weight and/or body Body situation selects the dosage of prostacyclin analogs by means of injecting selected volume.
Therefore, present invention offer includes the method for selecting individual specificity's dosage in particular according to subject weight. Means for the selection of this dosage are selection applied volumes.
Precursor formulation of the invention is highly advantageous, because they are in the form of final " prepare for applying " by them It is stable when long term storage.Therefore, they can be easy to be provided to by healthy professional or by patient or their nursing Person is administered, these people need not to be the healthy professional by training up, and can not have and prepare complicated preparation Experience or technical ability.This duration is permanent, the slow disease such as diabetes that take effect in the case where be especially important.
PDE5 inhibitor
In another aspect of this invention, precursor formulation of the invention will include at least one prostacyclin or prostacyclin class It is all as those described herein like object, and at least one PDE5 inhibitor can be additionally comprised.
PDE5 inhibitor has usually been administered carrys out immediate treatment erection function exception (ED), and is advantageously provided In rapid onset formulation.However, in the long-term treatment to several great illness of clinic including pulmonary hypertension (PAH) It indicates and/or tests in the PDE5 inhibitor being suitble under dosage.Therefore, the PDE5 inhibitor of suitable dosage can be added to any To provide economic benefits and social benefits treatment in invention formulation.
Being suitble to PDE5 inhibitor includes known inhibitor, such as avanaphil (avanafil), sieve that is non- (lodenafil), meter Luo Nafei (mirodenafil), silaenafil (sildenafil), tadalafil (tadalafil), cut down Ground that non-(vardenafil), udenafil (udenafil), Zaprinast (zaprinast), icariin (Icariin) (and its synthesis of derivatives), Ben Zhanafei (benzamidenafil), Da Shengtafei (dasantafil), its salt, prodrug and mixed Close object.The suitable PDE5 inhibitor of height includes tadalafil (Tadalafil (Cialis)) and Vardenafil (Ai Lida (Levitra))。
PDE5 inhibitor be suitable for applied dose will be usually 1 to 75mg PDE5 inhibitor (with free alkali once a week Or unprotected drug molecule meter), preferably weekly 2 to 50mg (i.e. application every time), and most preferably weekly 5 to 25mg model In enclosing.
PDE5 inhibitor be suitable for applied dose once every two weeks will be usually 2 to 150mg PDE5 inhibitor (with trip From alkali or unprotected drug molecule meter), preferably in every two weeks 5 to 100mg (i.e. applications every time), and most preferably every two weeks 10 To 50mg.
PDE5 inhibitor be suitable for monthly applied dose will be usually 5 to 300mg PDE5 inhibitor (with free Alkali or unprotected drug molecule meter), preferably monthly 10 to 200mg (i.e. application every time), and most preferably monthly 20 to In the range of 100mg.
Alternatively, storage tank precursor of the invention can be applied together (i.e. with the equivalent agent comprising at least one PDE5 inhibitor One application is the precursor formulation containing prostacyclin analogs, and another application is the preceding system containing PDE5 inhibitor Agent).The associated application can be for simultaneously, or sequentially with any order, but will be usually on the same day, and using having a class Like the storage tank precursor formulation (such as both will be that monthly preparation or both is weekly preparation) of duration.Preferably, phase To apply comprising similar control release matrix (such as both comprising lipid or both comprising polymer, such as with application Any optimum decision system indicated herein) precursor formulation will be and most preferably that apply be lipid formulations, and includes The precursor formulation of lipid composition (optional and identical or be substantially the same solvent composition) that is identical or being substantially the same.It is optimal Selecting component will include DAG as described herein (such as GDO) and phosphatide (such as PC).
Device
On the other hand, the present invention provides a kind of deserted with the precursor formulation preloaded of the invention through dosing Application device (it also will include device assembly).This device will usually contain the single dose for preparing to be used to apply, and will Usually it is subject to aseptic packaging so that composition storage is in the device until application.Appropriate means includes cylindrantherae, ampoule, and special It is syringe and injector cartridge, with integral pin or with being suitable for using standard (such as the Rule for being suitble to Disposable needle (luer)) connector.Similar device appropriate includes needleless injector, be used for multiple times or be intended for single use automatic injector with it is pre-filled Combinations of syringe, cylindrantherae optionally with pen device be used for multiple times combine or bottle.Obviously, the pre-filled syringe and cylindrantherae can For any appropriate injection device, such as it is used for multiple times or signal use syringe or Needleless injection device.
Apparatus of the present invention preferably contain delivering 2 to 50mg/ml, preferably 5 to 40mg/ml, most preferably 7 to 35 or The precursor formulation of the invention of dosage in the range of 10 to 30mg/ml.Dose volume will be usually at most 2ml (such as 0.1 to 2ml), such as 0.25 to 1.5ml or 0.5 to 1ml.The preparation applied weekly or more often is preferably at most in terms of volume 1.2ml or 1.0ml, wherein the preparation applied every two weeks or monthly is preferably at most 2ml or 1.5ml in terms of volume.
In an embodiment for being applicable to all aspects of the invention, apparatus of the present invention can contain 1 to 200mg Such as the prostacyclin analogs of the single dose of 2 to 150mg (such as 5 to 120mg).
Apparatus of the present invention, preferably 0.01 to 1mg/kg/ weeks, can especially exist containing under about 0.005 to 2.5mg/kg/ weeks Prostacyclin analogs under 0.015 to 0.7mg/kg/ weeks level.For 50kg, 70kg or 80kg subject and own The dosage of other subjects or subject weight's range can be calculated correspondingly.For example, prostacyclin analogs is suitable In 70kg subject dosage will 0.35 to 175mg/ weeks, preferably 0.7 to 70mg/ weeks, especially 1 to 50mg/ weeks model In enclosing.
Apparatus of the present invention can contain at most 2ml, total applied volume of preferably up to 1ml, especially up to 0.5ml.
Pre-filled device of the invention can also be suitably included in application medicine box, and the medicine box also forms of the invention another On the one hand.On the other hand, therefore, the present invention provides a kind of for applying the medicine box of at least one prostacyclin analogs, institute It states medicine box and contains invention formulation through dosing and optional application device or its component.Preferably, dosage will be received In the device or component that will be suitable for intramuscular or preferred subcutaneous administration.Medicine box may include additional application component such as needle, swab Deng, and will be optionally and preferably containing application specification.The specification will be usually directed to by approach as described herein into Capable application and/or to this paper disease indicated above treatment.
Medicine box
The present invention provide a kind of comprising precursor formulation as described herein such as the pre-filled application device that indicates herein and A kind of medicine box as indicated herein.Suitable medicine box may include being intended for single use or being used for multiple times injection device such as automatic injector, It or may include for the cylindrantherae or component in described device.
In addition medicine box of the present invention will include (optionally but preferably) any with lower component:
I) injection device, such as syringe or automatic injector
Ii) dose metering devices (such as graduation apparatus for measuring or being arranged applied volume)
Iii) for dose volume to be calculated and/or be arranged based on the parameter of such as subject weight and/or dose frequency Table, figure, telephony application or electronic calculator.In the calculating, can explicitly or implicitly consider such as disease into The factor of exhibition and/or prostacyclin analogs concentration.
Iv) about according to such as subject weight and/or dose frequency, progression of disease (such as mean pulmonary arterial pressure) and/ Or the factor of prostacyclin analogs concentration is administered and/or is stepped up the specification of administration.
Preferred feature and combination
It is combined with the feature and preferred feature indicated herein, precursor formulation of the invention can have independently or in combination One or more following preferred features:
The all proportions indicated herein all can optional variable specified amount up to 10%, optionally and preferably up to 5%；
Component a) includes GDO, is substantially made of GDO or is preferably made of GDO；
Component b) include it is following, be substantially made up of or be preferably made up of: Soybean PC and/or " high-purity PC " such as DOPC；
Component c) include it is following, be substantially made up of or be made up of: 1,2,3 or 4 carbon alcohol, preferably isopropyl Alcohol, or more preferably ethyl alcohol；
Component c) includes or mixtures thereof polar solvent such as water, NMP, DMSO, propylene glycol；
Precursor formulation has the low viscosity as indicated herein.
Precursor formulation forms the liquid crystalline phase as indicated herein after applying in vivo.
Precursor formulation generates storage tank after applying in vivo, and the storage tank was after at least 3 days, preferably at least 5 days, more preferably At least 7 days periods discharged at least one prostacyclin analogs.
Precursor formulation generates storage tank after apply in vivo to subject, and the storage tank discharges at least one forefront ring Plain analog so that after administration at the end of the 7th day in the subject plasma concentration of prostacyclin analogs be After application at the end of first day (at i.e. 24 hours after administration) in the subject prostacyclin analogs blood plasma Concentration is not less than 10-4Times or 10-3Times, preferably not less than 10-2Times, more preferably no less than 10-1Times.
It is combined with the feature and preferred feature indicated herein, treatment method of the invention can have independently or in combination One or more following preferred features:
Method includes at least one preparation with one or more preferred features as above instructions of application；
Method includes by intramuscular injection, is subcutaneously injected or preferably applies at least one by depth subcutaneous injection such as The preparation indicated herein；
Method includes being administered by means of the pre-filled application device such as indicated herein；
Method includes by no more than 20 specifications, preferably smaller than 20 specifications, and most preferably 23 specifications or smaller needle To apply；
Method includes every 3 to 10 days, preferably every 5 to 8 days progress single administrations.
Method include as the progress of disease those of (herein instruction) is stepped up dosage and frequency so that frequency to It is mostly stepped up weekly at least every 3 days and applies, and be stepped up from most 10 or 20mg/ weeks at least 30 or 40mg/ weeks.
It is combined with the feature and preferred feature indicated herein, the purposes of the precursor formulation manufacture medicament indicated herein can be only On the spot or in combination there are one or more following preferred features:
Purposes includes the purposes of at least one preparation with one or more preferred features as above instructions；
Purposes includes manufacture for being injected, being subcutaneously injected by intramuscular or is preferably applied to by depth subcutaneous injection A kind of medicament of few preparation such as indicated herein；
Purposes includes the medicament manufactured for being administered by means of the pre-filled application device such as indicated herein；
Purposes include manufacture for by be not more than 20 specifications, preferably smaller than 20 specifications, and most preferably 23 specifications or Smaller needle is come the medicament applied；
Purposes includes medicament of the manufacture for daily or every 2,3,7,14,21,28,30 or 60 days applied onces, and can Systematically or occasionally to be changed in a small amount (such as with ± 3 days, or with ± 20% in any appropriate situation).
It is combined with the feature and preferred feature indicated herein, pre-filled device of the invention can have independently or in combination There are one or more following preferred features:
They contain as herein referred to the preferred formulation shown；
They include less than 20 specifications, the preferably no greater than needle of 23 specifications；
They contain the prostacyclin analogs (based on free acid) under 2.5 to 50mg/ml of single dose, and such as 5 To 50mg/mL (being based on free acid).
They contain the homogeneous mixture that injection form is used in preparation with composition of the invention.
They contain component a) to c) for combining with prostacyclin analogs, whereby to form preceding system of the invention The preparation of agent.
They contain at most 5ml, preferably up to 3ml, such as at most 2ml, total applied volume of more preferably up to 1.5ml.
It is combined with the feature and preferred feature indicated herein, medicine box of the invention can have one kind independently or in combination Or a variety of following preferred features:
They contain as herein referred to the preferred formulation shown；
They contain as herein referred to the pre-filled device shown；
They contain less than 20 specifications, the preferably no greater than needle of 23 specifications；
They contain the prostacyclin analogs (as described herein) of 1 to 100mg single dose, and preferably 2 to 75mg, More preferably 3.5 to 60mg.
They contain " two-region room medicine box " comprising at least two contain lipid formulations and prostacyclin of the invention respectively The container of analog.
They contain at most 5ml, preferably up to 3ml, such as at most 2ml, total applied volume of more preferably up to 1.5ml.
They contain about by such as the approach indicated herein and/or the explanation applied under the frequency such as indicated herein Book；
They, which contain, applies specification about used in the treatment method as described herein.
It as used herein, will be usual about the term " about " of numerical value or numberical range, " about ", " generally " or " approximation " Indicate that specified number value or range is preferred, but this numerical value can change in a certain degree without substantially influencing correlative The property of matter, composition or similar products.Skilled worker author usually can be easy to determine the numerical value can be varied without Damage degree locating for key advantages of the invention.As general standard, the end value of the numerical value or the range is alterable ± 10%, preferably ± 5%, and more preferably ± 1%.Corresponding meaning is attributable to the composition of " being substantially grouped as by certain groups ", It may also comprise up to 10% in addition to those of specified component, preferably up to 5%, and most preferably up to 1% other groups Point.When chemical group, chain or other parts are described herein as optionally being substituted, the substitution may not be present or institute The one or more atoms (usually one or more hydrogen and/or carbon) stated in part can be replaced by group such as below: halogen Plain (such as F, Cl, Br, I) group, the part based on oxygen such as ether, alcohol, ester, carboxylic acid or epoxides, the group based on nitrogen are all Such as amine groups, amide group, nitrile group or nitro, or group mercaptan, disulfide, thioesters based on sulphur etc..Work as context When permission, up to about 10 substitutions, but usual 3 substitutions carried out with the substituent group of independent choice or a little can be carried out It will be typical for replacing such as 1,2 or 3 substitution.
The present invention is now further illustrated by referring to following non-limiting embodiment and attached drawing.
Embodiment
Material
Treprostinil sodium salt TPN (Na) from Sanofi；Soy phosphatidylcholine SPC from Lipoid Lipoid S100；Diolein GDO Cithrol GDO HP-SO- (LK) from Croda；Dioleoyl from NOF Base phosphatidyl choline DOPC；Ethyl alcohol EtOH (99.7%Ph.Eur) from Solveco；Propylene glycol PG from Fischer (Ph.Eur)；N-Methyl pyrrolidone NMP and dimethyl sulfoxide DMSO from Sigma-Aldrich be subject to as it is using.Institute Having other chemical substances all has analysis level purity.
Prepare precursor formulation
Lipid deposit mixture is prepared by the way that suitable SPC, GDO and solvent to be weighed into sterilizing vial.It connects Sealed vial is placed on roll mixer at room temperature (RT) until be thoroughly mixed into clear homogeneous liquid solution (< 24 Hour).TPN (Na) powder is added in corresponding lipid placebo preparation in new glass bottle.Then bottle is sealed, and And it is placed on roll mixer at room temperature until being thoroughly mixed into clear homogeneous liquid solution (< 24 hours).By preparation Preparation is stored in the dark until further experiment at room temperature.For exploratory stability assessment, preparation is dispensed to sterilizing In 2R vial (each bottle 1g preparation).Bottle is sealed, and is placed in controlled environment storage cabinet.It is taken predetermined Sampling point is taken out the preparation of two bottles from each storage cabinet, placed 1 hour at room temperature, and examined using gradient HPLC with UV It surveys to analyze content and purity.
Embodiment 1: assessment TPN (Na) dissolubility and release in vitro
It assesses dissolubility in the following manner: TPN (Na) being added in corresponding lipid deposit mixture, then in room It is mixed on roll mixer until being thoroughly mixed into clear homogeneous liquid solution under warm (RT).During preparation, to sample into Row visual inspection.TPN (Na) has good solubility, and at least 7wt% (about 78mg in a variety of precursor formulations as the result is shown TPN (0)/mL) drug load be feasible.As shown in table 1, depending on cosolvent type, concentration and composition, preparation Viscosity is measured between 185-628mPas.
The viscosity of various precursor formulations of the table 1. containing 7wt%TPN (Na).
Release in vitro test is carried out to TPN (Na) using the concise quantitative determination based on UV/VIS spectroscopic methodology.In testing, By the way that the corresponding precursor formulation of 0.03-0.10g (target value 0.1g) is injected to the 10mL being maintained in 20R glass syringe bottle Storage tank is prepared in PBS (pH 7.4).The precise volume for the preparation being added in each bottle is determined by weighing.Bottle is used into rubber Rubber plug and the sealing of aluminium compression-joint cover, and be placed under oscillation in the couveuse being maintained at 37 DEG C.In predetermined point of time to releasing Medium sampling is put, dilutes and is transferred in quartz colorimetric utensil, and in 25 dual-beam UV-VIS of Perkin Elmer Lambda It is analyzed at 273nm on spectrophotometer.
From release in vitro measurement as the result is shown in Fig. 1 a.According to result, it is evident that both quantity of solvent and composition Influence the initial in vitro release of treprostinil.Compared to the preparation with DMSO, have comprising PG as the preparation of cosolvent There are slower initial release (24 hours).In addition, when comparing the preparation with EtOH as exclusive solvents, compared with high solvent content Under, initial release is very fast.Fig. 1 b further indicate release in vitro be it is two stage, wherein solvent and drug discharge together just After stage beginning, release is linear with the square root of time, such as passes through the diffusion from whole storage tank matrix and controls release Desired by mechanism.
Embodiment 2: application has the precursor formulation of TPN (Na): preparation and changes of weight in rats
The main target of this investigative research is to assess in the precursor formulation single subcutaneous injection that will have TPN (Na) The locally and systemically tolerability of TPN after into rat (preparation composition is given in Table 2).Research is designed to dosage gradually Research is increased, wherein administration dosage is 3,9 and 27mg/kg TPN (table 3).
Table 2. is for the preparation composition in exploratory rat studies.
Table 3. is used for treatment group and TPN dosage in investigative research.
Fig. 2 is shown in the average relative body weight variation during research.Preparation B1 and B2 are monitored in investigative research as follows Injection site erythema/oedema:
Scoring Classification
0 Without erythema/oedema
1 Slight erythema/oedema (dimly distinguishable)
2 Moderate clearly determines erythema/oedema
3 Severe erythema is to slight eschar formation/severe edema
Erythema and oedema after applying preparation B1 and B2 form degree and indicate in the following table 4:
The general introduction of erythema and oedema of the table 4. during investigative research at injection site.
Angiogenesis/bleeding of preparation B1 and B2 are monitored in investigative research as follows:
The horizontal of angiogenesis is determined by 0 to 3 range:
0 represents without angiogenesis.
1 represents slight angiogenesis.Limited angiogenic growth.
2 represent Moderate vessel generation.Widened angiogenic growth.
3 represent severe angiogenesis.Extensive angiogenic growth.
The horizontal of bleeding is determined by 0 to 3 range:
0 represents without bleeding.
1 represents hyporrhea.One or more diffusion red area.
2 represent medium bleeding.At least one clearly determining red area.
3 represent severe bleeding.Several clearly determining red areas.
Angiogenesis and extent of hemorrhage after applying preparation B1 and B2 indicate in the following table 5.
The general introduction for the injection site result of study that table 5. obtains in investigative research in postmortem.
Embodiment 3: the influence to the nanostructure of fully hydrated precursor formulation changes with different amounts of TPN (Na)
Following preparation L to AA is prepared, composition and measurement viscosity provide in table 6 and Fig. 3 respectively.
Table 6. is used for the formulation code and composition of nanostructure assessment.
Use the nanostructure of fully hydrated preparation of the small angle x-ray diffraction (SAXD) assessment from table 6.It briefly, will about 100mg preparation is injected in 5mL PBS buffer solution, and indwelling to be to balance 8 days at ambient room temperature in static bottle, then Carry out SAXD measurement.The fully hydrated preparation changed with TPN (Na) concentration is studied using synchrotron SAXD measurement Nanostructure, the measurement is using the 1M PILATUS 2D detector (Dectris) containing total 981x1043 pixel in MAX (the Max II electron accelerator run at 1.5GeV, Lund University, Sweden) is in I911-4 light in the laboratory IV It is carried out under bunch.It is sub- that sample is placed in thin polyamides in customization steel sample clamper under sample and detector distance 1919.5mm Between amine film.Using X-ray wavelengthWith 0.25 × 0.25mm of beam cross section (halfwidth) record diffraction at sample Figure.The Lauda RE 420G thermostat (Lauda-Brinkmann, LP) to computerized control is set to realize temperature control.Exist in succession 25, at 37 and 42 DEG C, 60s exposure duration is used at each temperature, and waits between temperature jump 10 minutes to carry out reality It tests.The use of gained ccd image is by ESRF (European synchronous radiation from machine research department (European Synchrotron Radiation Facility), France) the Fit2D software that provides integrates and analyzes.The sample corrected using Silver behenate With detector distance and detector location.
Fig. 5 and Fig. 6 is shown with TPN concentration and temperature and the fully hydrated lipid/EtOH (90/10wt%) changed and rouge The gained SAXD result of the nanostructure of matter/EtOH/PG (85/7.5/7.5) preparation.Data in Fig. 5 are shown in 37-42 DEG C In temperature region, until the TPN of 3.1wt%, the fully hydrated preparation based on 10%EtOH forms anti-six side (H2) mutually and instead The mixture of micellar cubic (Fd3m) phase.At the TPN of 4.65 and 6.2wt%, single H2 is formed, in even higher concentration Unordered micellar solution (L2) is started to transform under TPN.In addition, the lattice parameter of Fd3m phase is kept not as TPN concentration increases Become, and the lattice parameter of H2 phase starts to increase.Lattice parameter increase since the TPN (Na) of 4.65wt% may be gelled The storage tank machinery softness observed in experiment increases related.In short, observed as TNP concentration increases from Fd3m's and H2 Mixture is associated with gained release in vitro result to the transformation of the mixture of H2 phase and L2 phase to single H2 and further, In find that discharged TPN sharply increases (Fig. 4) at the TPN of 6.2 and 7.75wt%.As a comparison, Fig. 6 is shown to 7.5/ The SAXD result that the fully hydrated preparation prepared under the EtOH/PG mixture of 7.5wt% obtains.Here, in 37-42 DEG C of temperature It spends in region, only up to the TPN of 1.55wt%, form Fd3m phase and H2 phase clearly concludes mixture.2.33wt%TPN with Increase TPN concentration between 6.2wt%TPN, observes the mixture of H2 phase with L2 phase.In addition, at the TPN of 7.75wt%, shape Layered (L α) the mutually mixture with L2 phase.In addition, the lattice parameter of hexagonal phase has started at the TPN (Na) of 3.10wt% Increase.Based on these results, the fully hydrated preparation that deducibility is prepared using 7.5/7.5EtOH/PG is being transformed into from persistently releasing Less TPN can be accommodated from the viewpoint of putting before less advantageous more swelling liquid crystalline phase (especially L α).
The release in vitro overview of preparation N, P, Q, R and S are measured, and is shown in Fig. 4 a- Fig. 4 b (cumulative release %).
Embodiment 4: the physics and chemical stability of the precursor formulation containing TPN (Na)
Study the storage stability (table 7 and table 8) of preparation BB, CC and DD by HPLC under the following conditions :≤- 25 DEG C (freezing conditions)；25 DEG C/60%RH；With 40 DEG C/75%RH.Result instruction from exploratory stability test uses 10% TPN in precursor formulation of the EtOH as solvent and the precursor formulation of the mixture with EtOH/PG all has good physical And chemical stability.When storing at 25 DEG C/60%RH and 40 DEG C/75%RH, TPN, which is shown, continues at least up to 3 months Good stability (table 9).
The formulation code and composition that table 7. is assessed for physics and chemical stability.
Formulation code and viscosity of the table 8. for physics and chemical stability assessment.
What table 9. changed over time under different conditions of storage from the preparation of exploratory stability study TPN measurement result (HPLC).
Embodiment 5: application has the precursor formulation of TPN (Na) in rats
Prepared preparation EE-HH (table 10) using different solvents composition, and to the application of one group of 24 rat and use it is more early Points-scoring system monitoring erythema, oedema, angiogenesis and the bleeding of embodiment.
Table 10. is for the preparation composition and TPN dosage in P of Rats K research.
Erythema degree of the table 11. after applying preparation EE-HH.
Oedema degree of the table 12. after applying preparation EE-HH.
Injection site of the table 13. when after applying preparation EE-HH in postmortem.
Embodiment 6: the P of Rats K data of the precursor formulation with TPN (Na).
The pharmacokinetic data for the preparation EE to HH of embodiment 7 applied to rat was collected after 14 days.Data are to scheme Solution mode is illustrated in Fig. 7, and corresponding release in vitro overview is illustrated in Fig. 8.
The PK parameter of 14. preparation EE-HH of table in rats.Data are schematically illustrated in Figure 10, and discharge hundred Divide and is illustrated in Figure 11 than overview.
Embodiment 7: subcutaneous injection has the precursor formulation of TPN (Na) in dog
Aiming at for this research is assessed in maximum tolerated dose toxicity research in the preceding system that will have TPN (Na) Agent (formulation code JJ forms TPN (Na)/GDO/SPC/EtOH/PG3.38/43.31/43.31/7.50/2.50wt%) is subcutaneous TPN exposure after being injected in beasle dog.For the TPN dosage (form calculus in the form of TPN acid) in dog research in table 15 In provide.Gained dose dependent PK overview and exposure (AUC0-168h) value are presented in Fig. 9 and Figure 10 respectively.
Table 15. is for the TPN dosage level and volume in dog PK research.

Claims (43)

1. a kind of precursor formulation, it includes:
A) monoacyl lipid, diacyl lipid or at least one of three acyl group lipids and/or tocopherol；
B) optionally at least one phosphatide；
C) at least one bio-compatible organic solvent；With
D) at least one prostacyclin analogs or its salt；
Wherein the precursor formulation forms or is capable of forming at least one liquid crystalline phase structure after contacting with excessive aqueous fluids.
2. precursor formulation as claimed in claim 1, wherein component d) contain the cis- condensed pentamethylene ring of 3,4-, OH group at 1 of the pentamethylene ring is similar with the prostacyclin of C1-10 group at 2 of the pentamethylene ring Object.
3. being less than such as precursor formulation required in any precedent claims wherein the prostacyclin analogs have The molecular weight of 500g/mol, and not polypeptide.
4. being based on prostacyclin analogs free acid, the precursor such as precursor formulation required in any precedent claims Preparation include 0.1 to 10% component d), preferably 0.2 to 6%, all in this way 0.2 to 5%, especially 0.2 to 4%.
5. wherein component d) includes following or is made up of: bent such as precursor formulation required in any precedent claims Prostacyclin (TPN) or its salt, preferably treprostinil sodium salt.
6. wherein component a) includes following or is made up of such as precursor formulation required in any precedent claims: in Property diacyl lipid and/or monoacyl lipid, preferably diolein (GDO) or dehydrated sorbitol mono-fatty acid ester (SMO)。
7. wherein component a) includes following or is made up of: two such as precursor formulation required in any precedent claims Acylglycerol, preferably GDO.
8. wherein component a) includes following or is made up of: single such as precursor formulation required in any precedent claims Acyl group hexitan, preferably dehydrated sorbitol mono-fatty acid ester (SMO).
9. such as required precursor formulation in any precedent claims, it includes 20 to 80wt% component a), preferably 35 to 55%, especially 38 to 52%, especially 40 to 50%.
10. wherein component b) includes following or is made up of: phosphorus such as precursor formulation required in any precedent claims Phosphatidylcholine (PC), phosphatidyl-ethanolamine (PE) or phosphatidylinositols (PI), most preferably Soybean PC.
11. wherein component b) includes following or is made up of, excellent such as precursor formulation required in any precedent claims Choosing is made up of: synthesis or highly purified PC, selected from the group that is made up of: DDPC, DEPC, DLOPC, DLPC, DMPC, DOPC, DPPC, DSPC, MPPC, MSPC, PMPC, POPC, PSPC, SMPC, SOPC, SPPC or combinations thereof.
12. such as required precursor formulation in any precedent claims, it includes 30 to 60wt% component b), preferably 35 to 55%, especially 38 to 52%, especially 40 to 50%.
13. wherein component c) includes at least one selected from by following such as precursor formulation required in any precedent claims The solvent of the group of composition is made of at least one solvent selected from the group being made up of: alcohol, amine, amide, sulfoxide and/or Ester.
14. precursor formulation as claimed is claim 13, wherein component c) includes following or is made up of: single methanol is molten Agent, preferably ethyl alcohol.
15. precursor formulation as claimed is claim 13, wherein component c) includes following or is made up of: ethyl alcohol, third Or mixtures thereof alcohol, isopropanol, benzyl alcohol.
16. precursor formulation as claimed is claim 13, wherein component c) includes following or is made up of: ethyl alcohol or second The mixture of pure and mild propylene glycol, it is preferable that wherein the ratio of ethyl alcohol and PG are 1:1 to 10:1, more preferably 1.5:1 to 8:1, most Preferably 2:1 to 5:1 (for example, about 3:1).
17. precursor formulation as claimed is claim 13, wherein component c) includes following or is made up of: single methanol solvent And sulfoxide, preferably ethyl alcohol and DMSO.
18. precursor formulation as claimed is claim 13, wherein component c) includes following or is made up of: single methanol solvent And amide, preferably ethyl alcohol and N- methyl-pyrrolidon.
19. such as required precursor formulation in any precedent claims, wherein component c) is in 1 to 30 weight %, preferably 2 to 20 weight % especially exist under the level of 5 to 15 weight %.
20. wherein the ratio of component a:b is in 40:60 to 60:40's such as precursor formulation required in any precedent claims In range, especially in the range of 45:55 to 55:45.
21. such as precursor formulation required in any precedent claims, wherein the precursor formulation has L2Phase structure.
22. excellent after being stored 3 months under 25 DEG C and 60%RH such as precursor formulation required in any precedent claims It is selected in after 6 months, especially after 12 months, for being measured as the activating agent measured by HPLC, the precursor formulation With at least 96%, preferably at least 97%, especially at least 98% stability.
23. storing 1 month, preferably 3 under 40 DEG C and 75%RH such as precursor formulation required in any precedent claims After a month, especially 6 months, for measuring as the activating agent measured by HPLC, the precursor formulation has at least 96%, preferably at least 97%, especially at least 98% stability.
24. there is at 20 DEG C 100 to 700mPas viscosity such as precursor formulation required in any precedent claims.
25. according to precursor formulation described in any precedent claims, in which:
Component a) includes Soybean PC or is made of Soybean PC；
Component b) includes GDO or is made of GDO；
Component c) includes ethyl alcohol；And
Component d) includes TPN or its salt or is made of TPN or its salt.
26. precursor formulation according to claim 25 is further included selected from by PG, DMSO or NMP group formed Cosolvent, wherein ethyl alcohol: the ratio of cosolvent is in the range of 30:70 to 70:30 (w/w).
27. the precursor formulation according to claim 25 or 26, wherein component d) includes TPN (Na) or is made of TPN (Na).
28. further including at least one PDE5 to precursor formulation described in any one of 27 according to claim 1 and inhibiting Agent.
29. a kind of by making to be exposed to excessive aqueous fluids institute to precursor formulation described in any one of 28 according to claim 1 The composition of formation, with liquid crystalline phase structure.
30. the prostacyclin as described in precursor formulation required in any one of claim 1 to 28 to lasting application is similar The purposes of object.
31. such as required precursor formulation in any one of claim 1 to 28 or such as combination required in claim 28 Object is used as medicament.
32. a kind of method for treating people or non-human mammalian subject comprising Xiang Suoshu subject application such as right It is required that precursor formulation required in any one of 1 to 28.
33. method as claimed in claim 32 is used to treat people or non-human mammalian subject in need to resist At least one illness selected from the following: pulmonary hypertension (PAH), severe PAH, Raynaud's disease, ischemic and related disorders.
34. wherein administration method is not intravenously to apply such as claim 32 or method of claim 33.
35. the method as described in any one of claim 32 to 34, wherein administration method is shallow-layer or depth subcutaneous injection, warp Application in surface applied or mouth.
36. the method as described in any one of claim 32 to 35 is related to every 1 to 60 day, preferably every 1,2,3,7,14, 21,28,30 or 60 days (such as ± 1 day, ± 3 days, or under any circumstance ± 20%), most preferably every 7 (± 1) day or every 14 (± 2) day or the application of every 30 (± 3) day.
37. the method as described in any one of claim 32 to 36, wherein the prostacyclin analogs or its salt are 0.005 To 2.5mg/kg/ weeks level, preferably 0.01 to 1mg/kg/ weeks, especially under 0.015 to 0.7mg/kg/ weeks level Application.
38. being used for such as precursor formulation required in any one of claim 1 to 28 as any in claim 32 to 37 In in required method.
39. such as precursor formulation required in any one of claim 1 to 28 to manufacture for forming storage tank in vivo The purposes of medicament, the storage tank is for treating at least one illness selected from the following: pulmonary hypertension (PAH), severe PAH, Raynaud's disease, ischemic and related disorders.
40. a kind of pre-filled application device contains such as precursor formulation required in any one of claim 1 to 28.
41. pre-filled application device according to claim 40 comprising syringe, the syringe include having 23G Or the needle of smaller rugosity.
42. the pre-filled application device according to claim 40 or claim 41 comprising≤1mL, preferably≤0.5mL According to claim 1 to precursor formulation described in any one of 28.
43. a kind of medicine box comprising such as application device required in any one of claim 40 to 42.
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